Compounds Useful for Treating Liver Diseases

ABSTRACT

This invention provides compounds, for example, of Formulae (A)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof. The invention further provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutically acceptable carrier or vehicle. The compounds and compositions disclosed herein are useful for treating or preventing various diseases and conditions, for example liver disease such as liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), and kidney diseases such as acute kidney injury (AKI).

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. application Ser. No.17/195,334, filed Mar. 8, 2021, and is a continuation-in part of, andclaims the priority benefit of, international application no.PCT/IB2020/000808, filed Sep. 25, 2020, which claims the prioritybenefit of U.S. provisional application No. 62/906,288, filed Sep. 26,2019, the contents of each of which are incorporated herein in theirentireties by reference thereto.

2. FIELD OF THE INVENTION

This invention provides novel compounds, for example compounds ofFormulae (A)-(H) and (J)-(AA), and pharmaceutically acceptable salts,solvates, esters, amides, and prodrugs thereof, such as2-(4-(3-hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoicacid (“Compound I”),3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-one(“Compound II”), and3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-ol(“Compound III”), and pharmaceutically acceptable salts, solvates,esters, amides, and prodrugs thereof. The invention further providespharmaceutical compositions comprising a novel compound describedherein, for example a compound of Formulae (A)-(H) and (J)-(AA) or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, such as Compound I, Compound II or Compound III, or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, and a pharmaceutically acceptable carrier or vehicle. Thecompounds and compositions disclosed herein are useful for treating orpreventing conditions, for example, liver disease such as liverfibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD)or non-alcoholic steatohepatitis (NASH).

3. BACKGROUND

Elevated levels of low-density lipoprotein cholesterol (LDL-C) andtriglycerides are associated with mixed dyslipidemia. Type IIbhyperlipidemia, a type of mixed dyslipidemia, is characterized byelevation of apolipoprotein B, very low-density lipoprotein cholesterol(VLDL-C), intermediate density lipoprotein cholesterol (IDL), and smalldense low-density lipoprotein (LDL) levels, in addition to elevation inLDL-C and triglyceride levels.

Liver diseases, such as a non-alcoholic fatty liver disease (NAFLD)comprise a spectrum of conditions ranging from relatively benignsteatosis to more severe non-alcoholic steatohepatitis (NASH), thelatter of which, if untreated, can lead to fibrosis, cirrhosis, liverfailure, or hepatocellular carcinoma. NAFLD and NASH can develop due tohepatic triglyceride overproduction and accumulation. NAFLD is stronglyassociated with features of obesity, diabetes, dyslipidemia,hyperlipidemia and metabolic syndrome, including obesity, insulinresistance, type-2 diabetes mellitus, and dyslipidemia. NASH can causethe liver to swell, become inflamed, become fibrotic, become damaged andbecome ultimately less functional. NASH tends to develop in people whoare overweight or obese, or have diabetes, mixed dyslipidemia, highcholesterol or high triglycerides or an inflammatory condition. NASH ismarked by hepatocyte ballooning and liver inflammation, which can leadto liver damage and progress to scarring and irreversible changes,similar to the damage caused by heavy alcohol use.

Liver steatosis and fibrosis can also be induced by drugs, such asamiodarone, valproate, tamoxifen, methotrexate, and somechemotherapeutic and antiretroviral agents (Amacher, D. E., et al.Semin. Liver Dis., 2014, 34, 205). Drug-induced hepatic steatosis can bereversible and may involve drug accumulation in the liver.

NAFLD, NASH, fatty liver, or drug-induced liver steatosis can lead tometabolic complications including elevation of liver enzymes, fibrosis,cirrhosis, hepatocellular carcinoma, and liver failure. Liver failure islife-threatening and therefore there is a need to develop therapies todelay development, prevent formation or reverse the condition of a fattyliver.

Peroxisome proliferator-activated receptors (PPARs) have been identifiedas targets for the treatment of cardiometabolic diseases includingdiabetes, insulin resistance, dyslipidemia, and liver diseases such asNAFLD and NASH. There are three types of PPARs: PPARα, PPARγ and PPARδ.Several PPAR agonists have been marketed, including fenofibrate (a PPARαagonist), bezafibrate (a PPAR pan agonist), pioglitazone (a PPARγagonist), and rosiglitazone (a PPARγ agonist). Recently, PPAR agonistssuch as seladelpar (a PPARδ agonist), lanifibranor (a pan agonist), andelafibranor (a dual PPARα/δ agonist) have been studied for the treatmentof NASH and primary biliary cholangitis (PBC). However, several clinicaltrials involving such PPAR agonists have failed due to toxicity orfailure to meet primary endpoint. For example, in a Phase 3 trial inadults with NASH and fibrosis, elafibranor did not demonstrate astatistically significant effect on the primary endpoint of NASHresolution without worsening of fibrosis(ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3).

PPARδ agonists have also been proposed as a treatment for acute kidneyinjury (AKI). See, e.g., WO 2018/067857. AKI is a common occurrence inICU patients, with an estimated incidence of >50% (Hoste et al., 2015,Intensive Care Med; 41:1411-1423). Furthermore, increasing AKI severityis associated with increased mortality. Sepsis is the major cause ofAKI, accounting for 45% to 70% of cases, and approximately 25% of sepsisis of intra-abdominal origin (Seymour et al., 2016, JAMA, 315:762-774;Bagshaw et al., 2007, Clin J Am Soc Nephrol, 2:431-439).Ischemia/reperfusion injury (IRI) can cause AKI and is a commoncomplication in subjects receiving an organ transplant, with anincidence of 50-75% after lung and heart transplantation (Gueler et al.,2014, Transplantation 98:337-338). The PPARδ agonist ASP1128 (also knownas MA-0217) (Astellas) is being studied as a possible treatment for AKIfollowing coronary artery bypass graft surgery and/or valve surgery(ClinicalTrials.gov identifier NCT03941483). To date, however, no PPARδagonist has been approved and marketed as a treatment for AKI

There remains a need for new preventions and treatments for liverdisorders, kidney disorders and other conditions associated with PPARs.

4. SUMMARY OF THE INVENTION

The present invention provides novel compounds and their use to treatvarious disorders, for example, liver disorders such as NASH, kidneydisorders such as AKI, and other conditions associated with PPARs.Without being bound by theory, the inventor believes that the clinicalusefulness of PPAR agonists such as elafibranor are limited by theirtoxicity such that doses often cannot be increased sufficiently to reachan effective dose. The subject invention provides novel compounds,including derivatives of elafibranor and related compounds, andderivatives of PPAR modulators described in WO 2011/020001, WO2017/06246, WO 2017/180818, and WO 2018/067857. Without being bound bytheory, the inventor believes that the compounds described herein canact as PPAR agonists and/or as PPAR agonist prodrugs, which haveadvantageous properties that result in improved bioavailability and/orhalf-life and/or safety and/or efficacy and/or improved therapeuticindexes, following administration. In particular, the compound may thushave an improved therapeutic index. The therapeutic index (TI) is aratio that compares the dose at which a compound becomes toxic againstthe dose at which it is effective. One common measure of TI isTD₅₀/ED₅₀, wherein TD₅₀ and ED₅₀ are the toxic and effective doses,respectively, for 50% of the population. The larger the TI, the safer acompound is. Compounds with a low TI can be difficult to use in clinicalpractice and often require monitoring of plasma concentration in orderto prevent toxicity. The one or more advantageous properties of thecompounds of the disclosure (compared to known PPAR agonists, such aselafibranor or one or more PPAR agonists described in WO 2011/020001, WO2011/020001, WO 2017/06246, WO 2017/180818, and/or WO 2018/067857) caninclude, for example, better solubility, better kinetics, betterabsorption, better PPAR receptor selectivity at pharmaceuticallyeffective doses, reduced drug metabolism by cytochrome P450 or otherenzymes such as reductases, reduced glucuronidation, reduced toxicity,or a combination thereof.

In various aspects, the invention provides compounds of Formula (A)-(H)and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters,amides, and prodrugs thereof.

In one aspect, the present invention provides compounds of Formula (A):

-   -   and pharmaceutically acceptable salts, solvates, esters, amides,        and prodrugs thereof, wherein:    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹ and R²        together with the carbon atom to which R¹ and R² are attached        form a C₃-C₇ cycloalkyl group;    -   X is —CH₂OH, —COOH, —COH, —COOR³, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In another aspect, the present invention also provides compounds ofFormula (B):

-   -   and pharmaceutically acceptable salts, solvates, esters, amides,        and prodrugs thereof, wherein:    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹ and R²        together with the carbon atom to which R¹ and R² are attached        form a C₃-C₇ cycloalkyl group;    -   X is —CH₂OH, —COH, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

The present invention provides2-(4-(3-hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoicacid (“Compound I”) and pharmaceutically acceptable salts, solvates,esters, amides, and prodrugs, thereof, wherein Compound I has thestructure:

The present invention also provides3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-one(“Compound II”) and pharmaceutically acceptable salts, solvates, esters,amides, and prodrugs thereof, wherein Compound II has the structure:

The present invention further provides3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-ol(“Compound III”) and pharmaceutically acceptable salts, solvates,esters, amides, and prodrugs thereof, wherein Compound III has thestructure

In another aspect, the present invention provides compounds of Formula(C)

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof wherein:

-   -   R¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or        benzothienyl, any of which is unsubstituted or substituted with        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈        alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl,        nitro, amino, phenyl or pyridyl;    -   R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with a 3-7        membered cycloalkyl, or C₁₋₆ alkyl substituted with phenyl,        naphthyl or pyridyl, any of which is unsubstituted or        substituted with C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₃ alkoxy, C₁₋₈        haloalkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl,        benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;    -   A is oxygen, sulfur or NR⁹ in which R⁹ is hydrogen or C₁₋₈        alkyl;    -   X is a C₁₋₈ alkylene chain which is unsubstituted or substituted        with C₁₋₈ alkyl, C₁₋₈ alkoxy or hydroxyl, and which has 0 or 1        double bonds;    -   Y is C(═O), C(═N—OR¹⁰), CH(OR¹¹), CH═CH, C≡C, or C(═CH₂) in        which each of R¹⁰ and R¹¹ is hydrogen or C₁₋₈ alkyl;    -   each of R³, R⁴ and R⁵ is independently hydrogen, C₁₋₈ alkyl,        C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈ alkenyl, C₂₋₈        alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro, amino,        phenyl, or pyridyl; optionally wherein at least one of R³, R⁴,        and R⁵ is not hydrogen;    -   B is CH or nitrogen;    -   Z is oxygen or sulfur;    -   each of R⁶ and R⁷ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈        haloalkyl;    -   R^(x) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In other aspects, the invention provides compounds of Formula (D)-(H)and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters,amides, and prodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

In further aspects, the invention provides compounds of Formula (D)-(H)and (J)-(AA), e.g., as described in Section 5.2 (including subparts) andpharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

The present invention further provides a compound having the structure

and pharmaceutically acceptable salts, solvates, esters, amides, andprodrugs thereof.

Each compound of Formula (A)-(H) and (J)-(AA), each compound ofCompounds I, II, III, IV, V, Va, Vb, VI, VII, and VIII, and eachcompound described in Sections 5-7 (including their subparts), or apharmaceutically acceptable salt, solvate, ester, amide, and prodrugthereof is a “compound of the invention”. Exemplary features ofcompounds of the invention are described in Section 5.2 and specificembodiments 1 to 50 in Section 7.1 and 1 to 209 in Section 7.2, infra.

The present invention also provides compositions comprising i) aneffective amount of a compound of the invention and ii) apharmaceutically acceptable carrier or vehicle (each composition being a“composition of the invention”). Exemplary features of pharmaceuticalcompositions of the disclosure are described in Section 5.3 and specificembodiments 51 to 54 in Section 7.1 and 210 to 213 in Section 7.2,infra.

The present invention further provides methods for treating orpreventing a liver disorder, dyslipidemia, dyslipoproteinemia, a renaldisease, a disorder of glucose metabolism, a disorder of lipidmetabolism, a disorder of glucid metabolism, a cardiovascular disease, avascular disease, a metabolic syndrome, a complication associated withmetabolic syndrome, a PPAR-associated disorder, septicemia, a thromboticdisorder, obesity, diabetic nephropathy, diabetic retinopathy,atherosclerosis, pancreatitis, a cerebrovascular disease, a disorderrelated to neovascularization, hypertension, cancer, inflammation, aninflammatory disease, a neurodegenerative disease, an autoimmunedisease, a neoplastic disease, muscle atrophy, cholestasis,mitochondrial dysfunction, an ocular disease, a lysosomal storagedisease, a kidney disease (e.g., acute kidney injury), or impotence,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

The present invention further provides methods for treating orpreventing hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention.

The present invention further provides methods for treating a subjecthaving or preventing a subject from having an abnormally highconcentration in a subject's blood plasma or blood serum of highlow-density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a)(Lp(a)), apolipoprotein (a), or very low-density lipoprotein (VLDL),comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

The present invention further provides methods for treating a subjecthaving or preventing a subject from having an abnormally lowconcentration in a subject's blood plasma or blood serum of high-densitylipoprotein (HDL), comprising administering to a subject in need thereofan effective amount of the compound of the invention or the compositionof the invention.

The present invention further provides methods for treating a subjecthaving or preventing a subject from having an abnormally reduced ordeficient lipoprotein lipase concentration or activity in a subject'sblood plasma or blood serum, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention.

The present invention provides methods for treating or preventinghypoalphalipoproteinemia, a lipoprotein abnormality associated withdiabetes, a lipoprotein abnormality associated with obesity, alipoprotein abnormality associated with Alzheimer's Disease, or familialcombined hyperlipidemia, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention.

The present invention further provides methods for reducing in asubject's blood plasma or blood serum an abnormally high concentrationof triglycerides, low-density lipoprotein cholesterol (LDL-C), verylow-density lipoprotein cholesterol (VLDL-C), non-high-densitylipoprotein cholesterol, (non-HDL-C), lipoprotein(a) (Lp(a)),apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II orapolipoprotein C-III, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention.

The present invention further provides methods for elevating in asubject's blood plasma or blood serum an abnormally low concentration ofa high-density lipoprotein (HDL) associated protein, HDL-cholesterol,apolipoprotein A-I, or apolipoprotein E, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention.

The present invention further provides methods for promoting clearanceof triglycerides from a subject's blood plasma or blood serum,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

The present invention further provides methods for increasing abnormallylow glucose metabolism or increasing abnormally low lipid metabolism ina subject, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention.

The present invention further provides methods for treating orpreventing one or more symptoms of inflammation, systemic lupuserythematosus, lupus nephritis, or arthritis, comprising administeringto a subject in need thereof an effective amount of a compound of theinvention or a composition of the invention.

The present invention further provides methods for reducing the fatcontent of meat in livestock, comprising administering to livestock aneffective amount of a compound of the invention or a composition of theinvention.

The present invention further provides methods for reducing cholesterolcontent of a fowl egg, comprising administering to a fowl species aneffective amount of a compound of the invention or a composition of theinvention.

Exemplary uses of the compounds and compositions of the disclosure aredescribed in specific embodiments 55 to 163 in Section 7.1 and specificembodiments 214 to 322 in Section 7.2, infra.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1. Definitions

The term “about” when immediately preceding a numerical value means±upto 20% of the numerical value. For example, “about” a numerical valuemeans±up to 20% of the numerical value, in some embodiments, ±up to 19%,±up to 18%, ±up to 17%, up to 16%, +up to 15%, up to 14%, ±up to 13%,±up to 12%, up to 11%, ±up to 10%, ±up to 9%, up to 8%, ±up to 7%, ±upto 6%, up to 5%, ±up to 4%, ±up to 3%, ±up to 2%, ±up to 1%, +up to lessthan 1%, or any other value or range of values therein.

Throughout the present specification, numerical ranges are provided forcertain quantities. These ranges comprise all subranges therein. Thus,the range “from 50 to 80” includes all possible ranges therein (e.g.,51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all valueswithin a given range may be an endpoint for the range encompassedthereby (e.g., the range 50-80 includes the ranges with endpoints suchas 55-80, 50-75, etc.).

The term “pharmaceutically acceptable salt” includes both an acid and abase addition salt. Pharmaceutically acceptable salts can be obtained byreacting the compound of the invention functioning as a base, with aninorganic or organic acid to form a salt, for example, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid,camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citricacid, formic acid, hydrobromic acid, benzoic acid, tartaric acid,fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.Pharmaceutically acceptable salts can also be obtained by reacting acompound of the invention functioning as an acid, with an inorganic ororganic base to form a salt, for example, salts of sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, ammonia, isopropylamine, trimethylamine, choline, betaine,etc. Inorganic base can include, but are not limited to, calciumhydroxide, postassium hydroxide, sodium hydroxide, and sodium carbonate.Organic base can include, but are not limited to, primary amines,secondary amines, tertiary amines, substituted amines includingnaturally-occurring substituted amines, and cyclic amines, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine,glucoasamine, N-alkylgucamines, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, and the like. Those skilled in the artwill further recognize that pharmaceutically acceptable salts can beprepared by reaction of the compounds of the invention with anappropriate inorganic or organic acid or base via any of a number ofknown methods.

The term “solvate” refers to a solvation complex. Solvates can be formedby solvation (the combination of solvent molecules with molecules orions of the compounds of the invention), or a solvate can be anaggregate that comprises a solute ion or molecule or a solventmolecules. The solvent can be water, in which case the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. Thesolvate can be formed via hydration, including via absorption ofmoisture. A pharmaceutically acceptable salt can also be a solvate.Where a solvate is obtained via crystallization from a solvent, thesolvent can be an alcohol, such as methanol or ethanol; an aldehyde; aketone, such as acetone; or an ester, such as ethyl acetate.

The compounds of the invention can have one or more asymmetric centersand can thus be enantiomers, racemates, diastereomers, otherstereoisomers and mixtures thereof. The compounds of the inventioninclude all such possible isomers (including geometric isomers), as wellas their racemic and optically pure forms whether or not they arespecifically depicted herein. Optically active (+) and (−), (R)- and(S)-, or (D)- and (L)-isomers can be prepared using chiral synthons orchiral reagents, or resolved using conventional techniques, for example,chromatography and fractional crystallization. Conventional techniquesfor the preparation or isolation of individual enantiomers includechiral synthesis from a suitable optically pure precursor or resolutionof the racemate using, for example, chiral high pressure liquidchromatography (HPLC). Likewise, the compounds of the invention includeall tautomeric forms.

The language “substantially free of its corresponding oppositeenantiomer” means having no more than about 10 mol %, in anotherembodiment no more than about 5 mol %, in another embodiment no morethan about 2 mol %, in another embodiment no more than about 1 mol %, inanother embodiment no more than about 0.5 mol % and in anotherembodiment no more than about 0.1 mol %, of its corresponding oppositeenantiomer.

The language “substantially free of its corresponding oppositestereoisomer” means having no more than about 10 mol %, in anotherembodiment no more than about 5 mol %, in another embodiment no morethan about 2 mol %, in another embodiment no more than about 1 mol %, inanother embodiment no more than about 0.5 mol % and in anotherembodiment no more than about 0.1 mol %, of its corresponding oppositestereoisomer.

The language “substantially free of its corresponding other olefinconfiguration” means having no more than about 10 mol %, in anotherembodiment no more than about 5 mol %, in another embodiment no morethan about 2 mol %, in another embodiment no more than about 1 mol %, inanother embodiment no more than about 0.5 mol % and in anotherembodiment no more than about 0.1 mol %, of its corresponding otherolefin configuration.

An “effective amount” when used in connection with a compound of theinvention means an amount of the compound of the invention that, whenadministered to a subject is effective to treat or prevent a disorder orcondition disclosed herein, alone or with another pharmaceuticallyactive agent.

An “effective amount” when used in connection with anotherpharmaceutically active agent means an amount of the otherpharmaceutically active agent that is effective to treat or prevent adisorder or condition disclosed herein, alone or in combination with acompound of the invention.

A “subject” is a human or non-human mammal, e.g., a bovine, horse,feline, canine, rodent, or non-human primate. The human can be a male orfemale, child, adolescent or adult. The female can be premenarcheal orpostmenarcheal.

“Mammal” includes a human, domestic animal such as a laboratory animal(e.g., mouse, rat, rabbit, monkey, dog, etc.) and household pet (e.g.,cat, dog, swine, cattle, sheep, goat, horse, rabbit), and anon-domestic, wild animal.

All weight percentages (i.e., “% by weight” and “wt. %” and w/w)referenced herein, unless otherwise indicated, are relative to the totalweight of the mixture or composition, as the case can be.

“Alkyl” refers to a fully saturated, straight or branched hydrocarbonchain having from one to twelve carbon atoms, and which is attached toan atom by a single bond. Alkyls with a number of carbon atoms rangingfrom 1 to 12 are included. An alkyl group with 1 to 12 carbon atoms is aC₁-C₁₂ alkyl (alternatively represented as C₁₋₁₂ alkyl), an alkyl groupwith 1 to 10 carbon atoms is a C₁-C₁₀ alkyl (alternatively representedas C₁₋₁₀ alkyl), an alkyl group with 1 to 6 carbon atoms is a C₁-C₆alkyl (alternatively represented as C₁₋₆ alkyl), an alkyl group with 1to 5 carbon atoms is a C₁-C₅ alkyl (alternatively represented as C₁₋₅alkyl), and so on. A C₁-C₅ alkyl includes C₅ alkyls, C₄ alkyls, C₃alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆ alkyl includesall moieties described above for C₁-C₅ alkyls but also includes Calkyls. A C₁-C₁₀ alkyl includes all moieties described above for C₁-C₅alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀ alkyls.Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties, but alsoincludes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂ alkylinclude methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise, analkyl group can be unsubstituted or substituted with a substituentdisclosed herein. In some embodiments, an alkyl group is unsubstituted.

Alkoxy” refers to RO in which R is alkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain having fromtwo to twelve carbon atoms, and having one or more carbon-carbon doublebonds. Each alkenyl group is attached to an atom by a single bond.Alkenyl groups with a number of carbon atoms ranging from 2 to 12 areincluded. An alkenyl group with 2 to 12 carbon atoms is a C₂-C₁₂ alkenyl(alternatively represented as C₂₋₁₂ alkenyl), an alkenyl group with 2 to10 carbon atoms is a C₂-C₁₀ alkenyl (alternatively represented as C₂₋₁₀alkenyl), an alkenyl group with 2 to 6 carbon atoms is a C₂—C alkenyl(alternatively represented as C₂₋₆ alkenyl) and an alkenyl group with 2to 5 carbon atoms is a C₂-C₅ alkenyl (alternatively represented as C₂-C₅alkenyl) and so on. A C₂-C₅ alkenyl includes C₅ alkenyls, C₄ alkenyls,C₃ alkenyls, and C₂ alkenyls. A C₂-C₆ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls but also includes C₆ alkenyls. AC₂-C₁₀ alkenyl includes all moieties described above for C₂-C₅ alkenylsand C₂-C₆ alkenyls, but also includes C₇, C₈, C₉ and C₁₀ alkenyls.Similarly, a C₂-C₁₂ alkenyl includes all the foregoing moieties, butalso includes C₁₁ and C₁₂ alkenyls. Non-limiting examples of C₂-C₁₂alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl),iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl,3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl,1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl,7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl,4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl,9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl,4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl,9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise, analkyl group can be unsubstituted or substituted with a substituentdisclosed herein. In some embodiments, an alkenyl group isunsubstituted.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalhaving from two to twelve carbon atoms, and having one or morecarbon-carbon triple bonds. Each alkynyl group is attached to an atom bya single bond. Alkynyl groups with a number of carbon atoms ranging from2 to 12 are included. An alkynyl group having 2 to 12 carbon atoms is aC₂-C₁₂ alkynyl (alternatively represented as C₂₋₁₂ alkynyl), an alkynylgroup with 2 to 10 carbon atoms is a C₂-C₁₀ alkynyl (alternativelyrepresented as C₂₋₁₀ alkynyl), an alkynyl group with 2 to 6 carbon atomsis a C₂-C₆ alkynyl (alternatively represented as C₂₋₆ alkynyl) and analkynyl group with 2 to 5 carbon atoms is a C₂-C₅ alkynyl (alternativelyrepresented as C₂₋₅ alkynyl). A C₂-C₅ alkynyl includes C₅ alkynyls, C₄alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆ alkynyl includes allmoieties described above for C₂-C₅ alkynyls but also includes C₆alkynyls. A C₂-C₁₀ alkynyl includes all moieties described above forC₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includes C₇, C₈, C₉ and C₁₀alkynyls. Similarly, a C₂-C₁₂ alkynyl includes all the foregoingmoieties, but also includes C₁₁ and C₁₂ alkynyls. Non-limiting examplesof C₂-C₁₂ alkenyl include ethynyl, propynyl, butynyl, pentynyl and thelike. Unless stated otherwise, an alkyl group can be unsubstituted orsubstituted with a substituent disclosed herein. In some embodiments, analkynyl group is unsubstituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. The aryl radicalcan be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which can include fused or bridged ring systems. Aryl radicals include,but are not limited to, aceanthrylenyl, acenaphthylenyl,acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl,fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl,phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, andtriphenylenyl. Unless stated otherwise, the aryl can be unsubstituted orsubstituted with a substituent disclosed herein. In some embodiments, anaryl group is unsubstituted.

“Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fullysaturated hydrocarbon radical consisting of carbon and hydrogen atoms,which can include fused or bridged ring systems, having from three totwenty carbon atoms, preferably having from three to ten carbon atoms,and which is attached to an atom by a single bond. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicalsinclude, for example, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless statedotherwise, a cycloalkyl group can be unsubstituted or substituted with asubstituent disclosed herein. In some embodiments, a cycloalkyl group isunsubstituted.

“Halo” or “halogen” represents chloro, fluoro, bromo or iodo.

“Haloalkyl” refers to an alkyl group in which one or more hydrogen atomsare replaced by halogen. Examples of haloalkyl groups includetrifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl (CH₂F),pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl(CH₂CH₂F), trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl(CF(CF₃)₂).

“Haloalkoxy” refers to RO in which R is a haloalkyl group.

“Heteroaryl” refers to a 5- to 20-membered ring system radical includinghydrogen atoms, one to thirteen carbon atoms, one to six nitrogen,oxygen or sulfur heteroatoms, and at least one aromatic ring. Theheteroaryl radical can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical can be optionally oxidized; the nitrogen atom can be optionallyquaternized. Examples of heteroaryl include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thienyl). Unless stated otherwise, a heteroaryl group canbe unsubstituted or substituted. In some embodiments, a heteroaryl groupis unsubstituted.

“Heterocyclyl” refers to a 3- to 20-membered non-aromatic, partiallyunsaturated, or aromatic ring radical which includes two to twelvecarbon atoms and from one to six nitrogen, oxygen or sulfur heteroatoms.Heterocycly include heteroaryls as defined herein. Unless statedotherwise, the heterocyclyl radical can be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which can include fused, bridged,and spiral ring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical can be optionally oxidized; the nitrogen atom canbe optionally quaternized; and the heterocyclyl radical can be partiallyor fully saturated. Examples of heterocyclyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise, a heterocyclyl groupcan be unsubstituted or substituted with a substituent disclosed herein.In some embodiments, a heterocyclyl groups is unsubstituted.

As used herein, the symbol

(a “point of attachment bond”) denotes a bond that is a point ofattachment between two chemical entities, one of which is depicted asbeing attached to the point of attachment bond and the other of which isnot depicted as being attached to the point of attachment bond. Forexample,

indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond.

5.2. The Compounds of the Invention

5.2.1. Compounds of Formula (A)

In some embodiments, the compound of the invention is a compound ofFormula (A):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein:

-   -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹ and R²        together with the carbon atom to which R¹ and R² are attached        form a C₃-C₇ cycloalkyl group;    -   X is —CH₂OH, —COOH, —COH, —COOR³, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compound of Formula (A) is a racemate or amixture of enantiomers or diastereomers. In some embodiments, thecompound of Formula (A) has an olefin isomer configuration of (Z) or(E). In some embodiments, the hydroxyl-bearing allylic carbon atom ofthe compound of Formula (A) has an (R)- or an (S)-stereochemistry.

In some embodiments, the compound of Formula (A) is a (Z)-isomer (orcis) and has the structure:

In some embodiments, the compound of Formula ((Z)-A) is substantiallyfree of its corresponding other olefin configuration (i.e., (E)-isomer).

In some embodiments, the compound of formula (A) is an (E)-isomer (ortrans) and has the structure:

In some embodiments, the compound of Formula ((E)-A) is substantiallyfree of its corresponding other olefin configuration (i.e., (Z)-isomer).

In some embodiments, the compound of Formula (A) has an hydroxyl-bearingallylic carbon atom having (R)-stereochemistry and has the structure:

In some embodiments, the compound of Formula ((R)-A) is substantiallyfree of its corresponding opposite stereoisomer, i.e., a compound ofFormula (A) whose hydroxyl-bearing allylic carbon atom has an(S)-stereochemistry.

In some embodiments, the hydroxyl-bearing allylic carbon atom of thecompound of Formula (A) has an (S)-stereochemistry and has thestructure:

In some embodiments, the compound of Formula ((S)-A) is substantiallyfree of its corresponding opposite stereoisomer, i.e., a compound ofFormula (A) whose hydroxyl-bearing allylic carbon atom has an(R)-stereochemistry.

In some embodiments, the compound of Formula (A) is a (Z)-isomer (orcis), has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry and has the structure:

In some embodiments, the compound of Formula ((Z)-(R)-A) issubstantially free of compounds of Formulae ((Z)-(S)-A), ((E)-(R)-A), or((E)-(S)-A).

In some embodiments, the compound of Formula (A) is a (Z)-isomer (orcis), has an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry and has the structure:

In some embodiments, the compound of Formula ((Z)-(S)-A) issubstantially free of compounds of Formulae ((Z)-(R)-A), ((Z)-(R)-A), or((Z)-(S)-A).

In some embodiments, the compound of Formula (A) is an (E)-isomer (orcis), has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry and has the structure:

In some embodiments, the compound of Formula ((E)-(R)-A) issubstantially free of compounds of Formulae ((E)-(S)-A), ((Z)-(R)-A), or((Z)-(S)-A).

In some embodiments, the compound of Formula (A) is an (E)-isomer (orcis), has an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry and has the structure:

In some embodiments, the compound of Formula ((E)-(S)-A) issubstantially free of compounds of Formulae ((E)-(R)-A), ((Z)-(R)-A), or((Z)-(S)-A).

In some embodiments of compounds of Formula (A), ((Z)-A), ((E)-A),((R)-A), ((S)-A), ((E)-(R)-A), ((E)-(S)-A), ((Z)-(R)-A), or ((Z)-(S)-A)each R¹ and R² is independently —C₁-C₆ alkyl. In some embodiments, eachR¹ and R² is independently —C₁-C₃ alkyl. In some embodiments, each R¹and R² is independently methyl.

In some embodiments of compounds of formula (A), ((Z)-A), ((E)-A),((R)-A), ((S)-A), ((E)-(R)-A), ((E)-(S)-A), ((Z)-(R)-A), or ((Z)-(S)-A),X is —CH₂OH, —COOH, —COH, or —COOR³, or —COOCH₂CONR⁴R⁵. In someembodiments, X is —CH₂OH, —COOH, —COOR³, —COOCH₂CONR⁴R⁵. In someembodiments, X is —CH₂OH or —COOH.

In some embodiments of compounds of Formula (A), ((Z)-A), ((E)-A),((R)-A), ((S)-A), ((E)-(R)-A), ((E)-(S)-A), ((Z)-(R)-A), or ((Z)-(S)-A),R³ is —C₁-C₆ alkyl. In some embodiments, R³ is methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, or t-butyl.

In some embodiments of compounds of Formula (A), ((Z)-A), ((E)-A),((R)-A), ((S)-A), ((E)-(R)-A), ((E)-(S)-A), ((Z)-(R)-A), or ((Z)-(S)-A),n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In someembodiments, n is 0 or 1.

5.2.1.1. Compound I

In some embodiments, the compound of the invention is Compound I havingthe structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

In some embodiments, Compound I is a racemate or a mixture ofenantiomers. In some embodiments, Compound I has an olefin isomerconfiguration of (Z) or (E). In some embodiments, Compound I has anhydroxyl-bearing allylic carbon atom having an (R)- or an(S)-stereochemistry.

In some embodiments, Compound I is a (Z)-isomer (or cis) and has thestructure:

In some embodiments, Compound I is a (Z)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (E)-isomer).

In some embodiments, Compound I is an (E)-isomer (or trans) and has thestructure:

In some embodiments, Compound I is an (E)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (Z)-isomer).

In some embodiments, Compound I has an hydroxyl-bearing allylic carbonatom having an (R)-enantiomer and has the structure:

In some embodiments, Compound I has an hydroxyl-bearing allylic carbonatom having an (R)-enantiomer and is substantially free of itscorresponding opposite enantiomer (i.e., (S)-enantiomer).

In some embodiments, Compound I has an hydroxyl-bearing allylic carbonatom having an (S)-enantiomer and has the structure:

In some embodiments, Compound I has an hydroxyl-bearing allylic carbonatom having an (S)-enantiomer and is substantially free of itscorresponding opposite enantiomer (i.e., (R)-enantiomer). In someembodiments, Compound I is a non-racemic mixture of its (R)-enantiomerand (S)-enantiomer. In some embodiments, the non-racemic mixture has anexcess of (R)-enantiomer relative to (S)-enantiomer. In someembodiments, the non-racemic mixture has an excess of (S)-enantiomerrelative to (R)-enantiomer.

In some embodiments, Compound I is a (Z)-isomer (or cis), has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer and hasthe structure:

In some embodiments, Compound ((Z)-(R)-I) is substantially free ofCompounds ((Z)-(S)-I), ((E)-(R)-I), or ((E)-(S)-I).

In some embodiments, Compound I is a (Z)-isomer, has an hydroxyl-bearingallylic carbon atom having an (S)-enantiomer and has the structure:

In some embodiments, Compound ((Z)-(S)-I) is substantially free ofCompounds ((Z)-(R)-I), ((E)-(R)-I), or ((E)-(S)-I).

In some embodiments, Compound I is an (E)-isomer (or trans), has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer and hasthe structure:

In some embodiments, Compound ((E)-(R)-I) is substantially free ofCompounds (E)-(S)-I), ((Z)-(R)-I), or ((Z)-(S)-I).

In some embodiments, Compound I is an (E)-isomer, has anhydroxyl-bearing allylic carbon atom having an (S)-enantiomer and hasthe structure:

In some embodiments, Compound ((E)-(S)-I) is substantially free ofCompounds ((E)-(R)-I), ((Z)-(R)-I), or ((Z)-(S)-I).

5.2.1.2. Compound III

In some embodiments, the compound of the invention is Compound IIIhaving the structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

In some embodiments, Compound III is a racemate or a mixture ofenantiomers. In some embodiments, Compound III has an olefin isomerconfiguration of (Z) or (E). In some embodiments, Compound III has anhydroxyl-bearing allylic carbon atom having an (R)- or an(S)-stereochemistry.

In some embodiments, Compound III is a (Z)-isomer (or cis) and has thestructure:

In some embodiments, Compound III is a (Z)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (E)-isomer).

In some embodiments, Compound III is an (E)-isomer (or trans) and hasthe structure:

In some embodiments, Compound III is an (E)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (Z)-isomer).

In some embodiments, Compound III has an hydroxyl-bearing allylic carbonatom having an (R)-enantiomer and has the structure:

In some embodiments, Compound III has an hydroxyl-bearing allylic carbonatom having an (R)-enantiomer and is substantially free of itscorresponding opposite enantiomer (i.e., (S)-enantiomer).

In some embodiments, Compound III has an hydroxyl-bearing allylic carbonatom having an (S)-enantiomer and has the structure:

In some embodiments, Compound III has an hydroxyl-bearing allylic carbonatom having an (S)-enantiomer and is substantially free of itscorresponding opposite enantiomer (i.e., (R)-enantiomer). In someembodiments, Compound III is a non-racemic mixture of its (R)-enantiomerand (S)-enantiomer. In some embodiments, the non-racemic mixture has anexcess of (R)-enantiomer relative to (S)-enantiomer. In someembodiments, the non-racemic mixture has an excess of (S)-enantiomerrelative to (R)-enantiomer.

In some embodiments, Compound III is an (Z)-isomer (or cis), has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer and hasthe structure:

In some embodiments, Compound ((Z)-(R)-III) is substantially free ofCompounds ((Z)-(S)-III), ((E)-(R)-III), or ((E)-(S)-III).

In some embodiments, Compound III is an (Z)-isomer, has anhydroxyl-bearing allylic carbon atom having an (S)-enantiomer and hasthe structure:

In some embodiments, Compound ((Z)-(S)-III) is substantially free ofCompounds ((Z)-(R)-III), ((E)-(R)-III), or ((E)-(S)-III).

In some embodiments, Compound I is an (E)-isomer (or trans), has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer and hasthe structure:

In some embodiments, Compound ((E)-(R)-III) is substantially free ofCompounds ((E)-(S)-III), ((Z)-(R)-III), or ((Z)-(S)-III).

In some embodiments, Compound III is an (E)-isomer, has anhydroxyl-bearing allylic carbon atom having an (S)-enantiomer and hasthe structure:

In some embodiments, Compound ((E)-(S)-III) is substantially free ofCompounds ((E)-(R)-III), ((Z)-(R)-III), or ((Z)-(S)-III).

5.2.2. Compounds of Formula (B)

In some embodiments, the compounds of the invention are compounds ofFormula (B):

or a pharmaceutically acceptable salt, solvate ester, amide, or prodrugthereof, wherein:

-   -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹ and R²        together with the carbon atom to which R¹ and R² are attached        form a C₃-C₇ cycloalkyl group;    -   X is —CH₂OH, —COH, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compound of Formula (B) is a racemate or amixture of enantiomers. In some embodiments, the compounds of Formula(B) has an olefin isomer configuration of (Z) or (E).

In some embodiments, the compounds of Formula (B) is a (Z)-isomer (orcis) and has the structure:

In some embodiments, the compounds of Formula (B) is a (Z)-isomer and issubstantially free of its corresponding other olefin configuration(i.e., (E)-isomer).

In some embodiments, the compounds of Formula (B) is an (E)-isomer (ortrans) and has the structure:

In some embodiments, the compounds of Formula (B) is an (E)-isomer andis substantially free of its corresponding other olefin configuration(i.e., (Z)-isomer).

In some embodiments of compounds of Formula (B), each R¹ and R² isindependently —C₁-C₆ alkyl. In some embodiments, each R¹ and R² isindependently —C₁-C₃ alkyl. In some embodiments, each R¹ and R² isindependently methyl.

In some embodiments of compounds of Formula (B), X is —CH₂OH, —COH, or—COOCH₂CONR⁴R⁵. In some embodiments, X is —CH₂OH.

In some embodiments of compounds of Formula (B), R³ is —C₁-C₆ alkyl. Insome embodiments, R³ is methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, or t-butyl.

In some embodiments of compounds of Formula (B), n is 0, 1, 2, or 3. Insome embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

5.2.2.1. Compound II

In some embodiments, the compound of the invention is Compound II havingthe structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

In some embodiments, Compound II has an olefin isomer configuration of(Z) or (E).

In some embodiments, Compound II is a (Z)-isomer (or cis) and has thestructure:

In some embodiments, Compound II is a (Z)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (E)-isomer).

In some embodiments, Compound II is an (E)-isomer (or trans) and has thestructure:

In some embodiments, Compound II is an (E)-isomer and is substantiallyfree of its corresponding other olefin configuration (i.e., (Z)-isomer).

5.2.3. Compounds of Formula (C)

In some embodiments, the compounds of the invention are compounds ofFormula (C):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein:

-   -   R¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or        benzothienyl, any of which is unsubstituted or substituted with        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈        alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl,        nitro, amino, phenyl or pyridyl;    -   R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with a 3-7        membered cycloalkyl, or C₁₋₆ alkyl substituted with phenyl,        naphthyl or pyridyl, any of which is unsubstituted or        substituted with C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₃ alkoxy, C₁₋₈        haloalkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl,        benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;    -   A is oxygen, sulfur or NR⁹ in which R⁹ is hydrogen or C₁₋₈        alkyl;    -   X is a C₁₋₈ alkylene chain which is unsubstituted or substituted        with C₁₋₈ alkyl, C₁₋₈ alkoxy or hydroxyl, and which has 0 or 1        double bonds;    -   Y is C(═O), C(═N—OR¹⁰), CH(OR¹¹), CH═CH, C≡C, or C(═CH₂) in        which each of R¹⁰ and R¹¹ is hydrogen or C₁₋₈ alkyl;    -   each of R³, R⁴ and R⁵ is independently hydrogen, C₁₋₈ alkyl,        C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈ alkenyl, C₂₋₈        alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro, amino,        phenyl, or pyridyl; optionally wherein at least one of R³, R⁴,        and R⁵ is not hydrogen;    -   B is CH or nitrogen;    -   Z is oxygen or sulfur;    -   each of R⁶ and R⁷ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈        haloalkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In the Formula (C), examples of the alkyl groups having 1-8 carbon atomsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl andpentyl.

Examples of the alkyl groups having 1-8 carbon atoms and a halogensubstituent include methyl, ethyl, propyl, isopropyl, butyl, and t-butylwhich are substituted with 1-3 halogens such as fluorine, chlorine, andbromine. Examples include trifluoromethyl, chloromethyl, 2-chloroethyl,2-bromoethyl and 2-fluoroethyl.

Examples of the alkoxy groups having 1-8 carbon atoms include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and pentyloxy.

Examples of the alkoxy groups having 1-8 carbon atoms and a halogensubstituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy andt-butoxy groups substituted with 1-3 halogen atoms such as fluorineatom, chlorine atom or bromine atom. Trifluoromethoxy, chloromethoxy,2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy are included.

Examples of the alkenyl groups having 2-8 carbon atoms include vinyl andallyl.

Examples of the alkynyl groups having 2-8 carbon atoms includepropargyl.

Examples of 3-7 membered cycloalkyl groups include cyclohexyl andcyclopentyl.

Examples of the alkyl groups having 1-8 carbon atoms and a 3-7 memberedcycloalkyl substituent include cyclohexylmethyl and cyclopentylmethyl.

The compound of the Formula (C) can be present in the form ofgeometrical isomers such as cis and trans and optical isomers. Theseisomers are included in the compounds provided. Further, the compoundsprovided can be in the form of pharmaceutically acceptable salts, suchas alkali metal salts, e.g., sodium or potassium salt.

In some embodiments, R^(X) is CH₂OH, COH, or COOCH₂CONR⁴R⁵. In otherembodiments, R^(X) is CH₂OH.

In some embodiments, the compound of Formula (C) is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

In some embodiments, the compound of Formula (C) is a compound shown inTable 1 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 1 Structure Name

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-one

3-(2-(4-chloro-2- hydroxyphenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-one

1-(3-allyl-4-(2- hydroxyethoxy)phenyl)-3-(2- (2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)propan- 1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((2-hydroxyethyl)thio)-3- methylphenyl)propan-1-one

3-(2-(4-chloro-2- hydroxyphenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-one

2-(4-(3-(2-(2,4- dichlorophenyl)-5- isopropyloxazol-4-yl)prop-1-en-1-yl)-2- methylphenoxy)ethan-1-ol

2-(4-(3-(4-isopropyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)prop-1-en-1-yl)-2- methylphenoxy)ethan-1-ol

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-(2-hydroxyethoxy)- 3-methylphenyl)propan-1-one

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)propan-1-one

2-(4-(3-(4-isopropyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)prop-1-en-1-yl)-2- methylphenoxy)-2- methylpropan-1-ol

1-(4-(2-hydroxyethoxy)-2- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-2- methylphenyl)propan-1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-2-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-2- methylphenyl)propan-1-one

1-(4-(2-hydroxyethoxy)-3- propylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(3-allyl-4-(2- hydroxyethoxy)phenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

2-(4-(4-(2-(2,4- dichlorophenyl)-5- isopropyloxazol-4-yl)but-1-en-2-yl)-2-methylphenoxy)ethan- 1-ol

2-(4-(4-(2-(2,4- dichlorophenyl)-5- isopropyloxazol-4-yl)but-1-en-2-yl)-2-methylphenoxy)-2- methylpropan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)-2- methylpropan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3-methylphenyl)-2- methylpropan-1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)prop-2-en-1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)prop-2-en-1-one

1-(4-(3-hydroxypropoxy)-3- methylphenyl)-3-(4-isopropyl-2-(4-methoxyphenyl)thiazol-5- yl)propan-1-one

3-(2-(3,5-difluorophenyl)-4- isopropylthiazol-5-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-one

3-(2-(3,5-difluorophenyl)-4- isopropylthiazol-5-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl-2-(naphthalen-2-yl)thiazol-5- yl)propan-1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(naphthalen-2-yl)thiazol-5-yl)propan-1-one

3-(2-(4-butylphenyl)-4- isopropylthiazol-5-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-one

3-(2-(4-butylphenyl)-4- isopropylthiazol-5-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-one

1-(3-chloro-4-(2- hydroxyethoxy)phenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(3-chloro-4-((1-hydroxy-2- methylpropan-2-yl)oxy)phenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

1-(3-chloro-4-(2- hydroxyethoxy)phenyl)-3-(2- (2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)propan- 1-one

1-(3-chloro-4-((1-hydroxy-2- methylpropan-2- yl)oxy)phenyl)-3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)propan- 1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(5-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 4-yl)propan-1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(5-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-4-yl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropylthiazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-one

3-(2-(2,4-dichlorophenyl)-5- isopropylthiazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-one

1-(3-(2-hydroxyethoxy)-4- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(3-((1-hydroxy-2- methylpropan-2-yl)oxy)-4-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

1-(4-((1-hydroxypropan-2- yl)oxy)-3-methylphenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-methyl-2- (4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

2-(4-(3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)prop-1-en-1-yl)-2- methylphenoxy)-2- methylpropan-1-ol

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(3-((1-hydroxy-2- methylpropan-2-yl)oxy)-4-methylphenyl)propan-1-one

3-(4-ethyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-(2-hydroxyethoxy)- 3-methylphenyl)propan-1-one

3-(4-ethyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)propan-1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl-2-(p-tolyl)thiazol-5-yl)propan- 1-one

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(p-tolyl)thiazol-5-yl)propan- 1-one

2-((3-(2-(2-(2,4- dichlorophenyl)-5- isopropyloxazol-4-yl)ethyl)-5-methylbenzo[d]isoxazol-6- yl)oxy)ethan-1-ol

1-(4-(2-hydroxyethyl)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

(R)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-ol

5-chloro-2-(4-(3-hydroxy-3-(4- (2-hydroxyethoxy)-3-methylphenyl)propyl)-5- isopropyloxazol-2-yl)phenol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-ol

1-(3-allyl-4-(2- hydroxyethoxy)phenyl)-3-(2- (2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)propan- 1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((2-hydroxyethyl)thio)-3- methylphenyl)propan-1-ol

5-chloro-2-(4-(3-hydroxy-3-(4- ((1-hydroxy-2-methylpropan- 2-yl)oxy)-3-methylphenyl)propyl)-5- isopropyloxazol-2-yl)phenol

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-(2-hydroxyethoxy)- 3-methylphenyl)propan-1-ol

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)propan-1-ol

1-(4-(2-hydroxyethoxy)-2- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-2- methylphenyl)propan-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-2-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-2- methylphenyl)propan-1-ol

1-(4-(2-hydroxyethoxy)-3- propylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

1-(3-allyl-4-(2- hydroxyethoxy)phenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)-2- methylpropan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3-methylphenyl)-2- methylpropan-1-ol

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)prop-2-en-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)prop-2-en-1-ol

1-(4-(3-hydroxypropoxy)-3- methylphenyl)-3-(4-isopropyl-2-(4-methoxyphenyl)thiazol-5- yl)propan-1-ol

3-(2-(3,5-difluorophenyl)-4- isopropylthiazol-5-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-ol

3-(2-(3,5-difluorophenyl)-4- isopropylthiazol-5-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-ol

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl-2-(naphthalen-2-yl)thiazol-5- yl)propan-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(naphthalen-2-yl)thiazol-5-yl)propan-1-ol

3-(2-(4-butylphenyl)-4- isopropylthiazol-5-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-ol

3-(2-(4-butylphenyl)-4- isopropylthiazol-5-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-ol

1-(3-chloro-4-(2- hydroxyethoxy)phenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

1-(3-chloro-4-((1-hydroxy-2- methylpropan-2-yl)oxy)phenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-ol

1-(3-chloro-4-(2- hydroxyethoxy)phenyl)-3-(2- (2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)propan- 1-ol

1-(3-chloro-4-((1-hydroxy-2- methylpropan-2- yl)oxy)phenyl)-3-(2-(2,4-dichlorophenyl)-5- isopropyloxazol-4-yl)propan- 1-ol

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(5-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 4-yl)propan-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(5-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-4-yl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropylthiazol-4-yl)-1-(4-(2-hydroxyethoxy)-3- methylphenyl)propan-1-ol

3-(2-(2,4-dichlorophenyl)-5- isopropylthiazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2- yl)oxy)-3- methylphenyl)propan-1-ol

1-(3-(2-hydroxyethoxy)-4- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

1-(3-((1-hydroxy-2- methylpropan-2-yl)oxy)-4-methylphenyl)-3-(4-isopropyl- 2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)propan-1-ol

1-(4-((1-hydroxypropan-2- yl)oxy)-3-methylphenyl)-3-(4- isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-methyl-2- (4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

3-(4-hexyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(3-((1-hydroxy-2- methylpropan-2-yl)oxy)-4-methylphenyl)propan-1-ol

3-(4-ethyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-(2-hydroxyethoxy)- 3-methylphenyl)propan-1-ol

3-(4-ethyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)propan-1-ol

1-(4-(2-hydroxyethoxy)-3- methylphenyl)-3-(4-isopropyl-2-(p-tolyl)thiazol-5-yl)propan- 1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-isopropyl- 2-(p-tolyl)thiazol-5-yl)propan- 1-ol

1-(4-(2-hydroxyethyl)-3- methylphenyl)-3-(4-isopropyl- 2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-ol

5.2.4. Compounds of Formula (D)

In some embodiments, the compounds of the invention are compounds ofFormula (D):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹ and R² independently is a hydrogen, a halogen, nitro,        C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1 to 3 halogens,        C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈ alkenyl, C₂₋₈        alkynyl, 3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with        3-7 membered cycloalkyl, C₆₋₁₀ aryl which is optionally        substituted, arylalkyl group which has a C₆₋₁₀ aryl moiety and        C₁₋₃ alkyl moiety, a heterocyclic group or a heterocyclic-alkyl        group having a C₁₋₈ alkyl group;    -   each occurrence of R³, R⁴, and R⁵ is independently a hydrogen or        C₁₋₈ alkyl;    -   A is an oxygen atom, a sulfur atom, or NR³;    -   each of X¹, X², and Z independently is C(═O), C(═O)NH,        C(═N—OR⁴), CH(OR⁵), NH(C═O), NHSO₂, SO₂NH, CH═CH, C≡C, or a        bond; and Y is C₁₋₈ alkylene;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

Examples of the halogen atom for R¹ and R² include fluorine, chlorine,and bromine.

Examples of alkyl groups having 1-8 carbon atoms for R¹, R², R³, R⁴ andR⁵ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,and pentyl.

Examples of alkoxy groups having 1-8 carbon atoms for R¹ and R² includemethoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,t-butyloxy, and pentyloxy.

Examples of alkyl groups having 1-8 carbon atoms which has 1-3 halogensubstituents for R¹ and R² include chloromethyl, fluoromethyl,bromomethyl, chloroethyl, 2-fluoroethyl, and trifluoromethyl.

Examples of alkoxy groups having 1-8 carbon atoms which has 1-3 halogensubstituents for R¹ and R² include chloromethoxy, fluoromethoxy,bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, and trifluoroethoxy.

Examples of alkenyl groups having 2-8 carbon atoms for R¹ and R² includevinyl or allyl. The alkynyl group having 2-8 carbon atoms can be, forexample, propargyl. The cycloalkyl group having 3-7 carbon atoms can be,for example, cyclohexyl or cyclopentyl. The alkyl group having a 3-7membered cycloalkyl substituent can be, for example, cyclohexylmethyl orcyclopentylmethyl.

The aryl group for the aryl group optionally having a substituent for R¹and R² can be, for example, phenyl or naphthyl.

Examples of arylalkyl groups optionally having a substituent includebenzyl and phenethyl.

Example of heterocyclic groups for the heterocyclic group optionallyhaving a substituent include a 5-7 membered cyclic group havingring-forming 1-4 hetero atoms such as nitrogen, oxygen and sulfur. Forinstance, pyridyl, thienyl and furyl can be included. Further, a benzenering condensed with the heterocyclic group such as quinolyl orbenzothienyl can be included.

Examples of heterocyclic groups for the heterocyclic ring-alkyl group(the alkyl moiety has 1-8 carbon atoms) optionally having a substituentcan be the same as that described hereinbefore for the heterocyclicgroup optionally having a substituent. The alkyl group preferably has1-3 carbon atoms.

The substituent for the substituents of the aryl group optionally havinga substituent, the arylalkyl group (the aryl moiety has 6-10 carbonatoms, and the alkyl moiety has 1-8 carbon atoms) optionally having asubstituent, the heterocyclic group optionally having a substituent, anda heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms)optionally having a substituent can be a halogen atom such as chlorine,bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino grouphaving 1-8 carbon atoms such as methylamino, or ethylamino, adialkylamino group having 2-10 carbon atoms such as dimethylamino, analkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl,isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such asmethoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having1-8 carbon atoms which has 1-3 halogen substituents such aschloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl,or trifluoromethyl, an alkoxy group having 1-8 carbon atoms which has1-3 halogen substituents such as chloromethoxy, fluoromethoxy,bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy, analkyenyl group having 2-8 carbon atoms such as vinyl or allyl, analkynyl group having 2-8 carbon atoms such as propargyl, a cycloalkylgroup having 3-7 carbon atoms such as cyclohexyl or cyclopentyl, analkyl group having a cycloalkyl group of 3-7 carbon atoms such ascyclohexylmethyl or cyclopentylmethyl, phenyl, or pyridyl.

In some embodiments, the compound of Formula (D) is a compound shown inTable 2 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 2 Structure Name

3-(2-(2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl) propan-1-one

3-(2-(2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)-1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl) propan-1-ol

1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)phenyl)-3- (4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl) propan-1-one

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)-3-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl) propan-1-ol

5.2.5. Compounds of Formula (E)

In some embodiments, the compounds of the invention are compounds ofFormula (E):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹¹ and R¹² independently is hydrogen, halogen, nitro,        hydroxyl, amino, C₁₋₈ alkyl, an C₁₋₈ alkoxy, C₁₋₈ haloalkyl        group having 1 to 3 halogens, C₁₋₈ haloalkoxy group having 1 to        3 halogens, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a 3-7 membered        cycloalkyl, C₁₋₈ alkyl having a 3-7 membered cycloalkyl        substituent, or phenyl, naphthyl, benzyl, phenethyl, pyridyl,        thienyl, furyl, quinolyl, or benzothienyl group which optionally        has a substituent which is a halogen atom, nitro, hydroxyl,        amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1 to 3        halogens, C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, 3-7 membered cycloalkyl group, C₁₋₈ alkyl group        having a 3-7 membered cycloalkyl substituent, phenyl or pyridyl;    -   each of X¹ and Z¹ independently is C(═O), C(═O)NH, C(═N—OR¹⁴),        CH(OR¹⁵), NH(C═O), NHSO₂, SO₂NH, CH═CH, C≡C, or a bond, wherein        each of R¹⁴ and R¹⁵ is a hydrogen or C₁₋₈ alkyl;    -   Y¹ is C₁₋₈ alkylene;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the halogen atom, alkoxy groups having 1-8 carbonatoms, alkyl group having 1-8 carbon atoms which has 1-3 halogensubstituents, alkoxy group having 1-8 carbon atoms which has 1-3 halogensubstituents, alkenyl group having 2-8 carbon atoms, alkynyl grouphaving 2-8 carbon atoms, cycloalkyl group having 3-7 carbon atoms, alkylgroup having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbonatoms for R¹¹ and R¹² can be those described for the halogen atom,alkoxy group, alkyl group having 1-8 carbon atoms which has a halogensubstituent, alkoxy group having 1-8 carbon atoms which has a halogensubstituent, alkenyl, alkynyl, cycloalkyl group, and alkyl group having1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R¹and R² of Formula (D).

In some embodiments, the alkyl group having 1-8 carbon atoms for R¹¹,R¹², R¹⁴, and R¹⁵ can be an alkyl group described for R¹, R², R³, R⁴ andR⁵ of Formula (D).

In the case that R¹¹ or R¹² is phenyl, naphthyl, benzyl, phenethyl,pyridyl, thienyl, furyl, quinolyl, or benzothienyl, these rings can insome embodiments have such substituents a halogen atom such as chlorine,bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino grouphaving 1-8 carbon atoms such as methylamino, or ethylamino, adialkylamino group having 2-10 carbon atoms such as dimethylamino, analkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl,isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such asmethoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having1-8 carbon atoms which has 1-3 halogen substituents such aschloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl,or trifluoromethyl, an alkoxy group having 1-8 carbon atoms which has1-3 halogen substituents such as chloromethoxy, fluoromethoxy,bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy, analkyenyl group having 2-8 carbon atoms such as vinyl or allyl, analkynyl group having 2-8 carbon atoms such as propargyl, a cycloalkylgroup having 3-7 carbon atoms such as cyclohexyl or cyclopentyl, analkyl group having a cycloalkyl group of 3-7 carbon atoms such ascyclohexylmethyl or cyclopentylmethyl, phenyl, or pyridyl.

The compound provided can be a stereoisomer such as cis or trans, or anoptical isomer. These isomers are included in the invention.

The compound provided includes a pharmaceutically acceptable salt suchas an alkali metal salt, e.g., sodium salt or potassium salt. Further,the compounds provided can be in the form of pharmaceutically acceptablesalts such as alkali metal salts, e.g., sodium salt and potassium salt.

In some embodiments, the compound of Formula (E) is a compound shown inTable 3 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 3 Structure Name

4-(2-(2-chlorophenyl)-5-isopropyloxazol-4-yl)-1-(4-(2-hydroxyethyl)phenyl)butan-1-one

4-(2-(2-chlorophenyl)-5-isopropyloxazol-4-yl)-1-(4-(2-hydroxyethyl)phenyl)butan-1-ol

5.2.6. Compounds of Formula (F)

In some embodiments, the compounds of the invention are compounds ofFormula (F):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A is O, S or NR⁷ in which R7 is hydrogen or C₁₋₈ alkyl;    -   B¹ is CW or N in which W is hydrogen or a bond; B² is O, S or        NR⁸ in which R⁸ is hydrogen or C₁₋₈ alkyl;    -   each of X¹ and X² is O, S, NH, NHC(═O), C(═O), C(═N—OR⁹),        CH(OR¹⁰), C═C, C≡C or a bond, wherein each of R⁹ and R¹⁰ is        hydrogen or C₁₋₈ alkyl;    -   Y is C₁₋₈ alkylene, which is unsubstituted or substituted with        C₁₋₈ alkyl or C₁₋₈ haloalkyl having 1-3 halogens;    -   Z is NH, O or S;    -   R¹ is aryl, which is unsubstituted or substituted with C₁₋₈        alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1-3 halogens,        hydroxyl, nitro, amino, phenyl, pyridyl or halogen, or a        heterocyclic group having a five to eight membered ring        comprising one to three hetero atoms each of which is        independently nitrogen, oxygen or sulfur and the other atoms are        carbon, optionally wherein a benzene ring is condensed with the        heterocyclic ring;    -   R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl having with 1-3 halogens, C₃₋₇        cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkyl substituted        with aryl, which is unsubstituted or substituted with C₁₋₈        alkyl, C₁₋₃ alkoxy, C₁₋₈ haloalkyl having 1-3 halogens,        hydroxyl, nitro, amino, phenyl, pyridyl or halogen, or C₁₋₄        alkyl substituted with a heterocyclic group having five to eight        membered ring having one to three heteroatoms each of which is        independently nitrogen, oxygen or sulfur;    -   R³ is halogen, trifluoromethyl, C₁₋₈ alkyl, C₂₋₃ alkenyl or C₂₋₃        alkynyl;    -   each of R⁴ and R⁵ is hydrogen, C₁₋₈ alkyl or C₁₋₈ haloalkyl        having 1-3 halogens;    -   each of Z and R³ is attached to the benzene ring, and X² is not        attached to the benzene ring;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In the Formula (F), R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, the substituent ofthe alkylene chain of Y, the substituent of the aryl and theheterocyclic group of R³, the substituent of the alkyl group substitutedwith aryl of R², and the substituent of the alkyl group substituted witha heterocyclic group of R² can in some embodiments be an alkyl grouphaving 1-8 carbon atoms. Examples of the alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

In some embodiments, R² can be an alkyl group having 2-8 carbon atoms.Examples of the alkyl groups include ethyl, propyl, iso-propyl, butyl,isobutyl, t-butyl, pentyl and hexyl.

In some embodiments, R², R⁴, R⁵, the substituent of the alkylene chainof Y, the substituent of the aryl or heterocyclic group of R¹, thesubstituent of the alkyl group substituted with aryl of R², and thesubstituent of the alkyl group substituted with a heterocyclic group ofR² can be an alkyl groups having 1-8 carbon atoms substituted with 1-3halogens. Examples of the haloalkyl groups include methyl. ethyl,propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3halogens such as fluorine, chlorine, and bromine. In some embodiments,the group is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethylor 2-fluoroethyl.

In some embodiments, R² and R³ can be an alkenyl group having 2-8 carbonatoms. Examples of the alkenyl groups include vinyl and allyl. R² and R³can be an alkynyl group having 2-8 carbon atoms. Examples of the alkynylgroups include propargyl.

In some embodiments, R³ can be a halogen atom. Examples of the halogenatoms include fluorine, chlorine and bromine.

In some embodiments, R² can be a cycloalkyl group having 3-7 carbonatoms. Examples of the cycloalkyl groups include cyclopropyl,cyclopentyl and cyclohexyl.

In some embodiments, the substituent of the aryl or heterocyclic groupof R¹, the substituent of the alkyl group substituted with aryl of R²,and the substituent of the alkyl group substituted with a heterocyclicgroup of R² can be an alkoxy groups having 1-8 carbon atoms. Examples ofthe alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, t-butoxy, pentyloxy and hexyloxy.

In some embodiments, R¹ and the aryl moiety of the aryl substituted withalkyl of R² can be an aryl group. Examples of the aryl groups includephenyl and naphthyl. R¹ and the substituent of the alkyl group of R² canbe a heterocyclic group having five to eight membered ring. Examples ofthe heterocyclic groups include pyridyl, thienyl, furyl, thiazolyl andquinolyl.

In some embodiments, R¹ can be a heterocyclic group having five to eightmembered ring comprising one to three hetero atoms selected from thegroup consisting of nitrogen, oxygen and sulfur and the other atomsconsisting of carbon. A benzene ring can be condensed with theheterocyclic ring. Examples of the condensed rings include quinolinering and benzothiophene ring

In some embodiments, Y can be an alkylene chain having 1 to 8 carbonatoms. Examples of the alkylene chains include methylene and ethylene.

In some embodiments, R³ can be one to three groups. In some embodiments,two or three groups of R³ can be different from each other.

In some embodiments, R⁶ can be an alkyl group having 1-8 carbon atomssubstituted with amino. Examples of the aminoalkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl andhexyl which are substituted with an amino group such as piperidino,pyrrolidino, dimethylamino, and diethylamino.

In some embodiments, the compounds of the Formula (F) can be in the formof pharmaceutically acceptable salts such as alkali metal salts, e.g.,sodium salt and potassium salt.

In some embodiments, the compound of Formula (F) is a compound shown inTable 4 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 4 Structure Name

2-((3-(2-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl)oxy)- 2-methylpropan-1-ol

2-((3-(2-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl)oxy)ethan-1-ol

2-((3-(2-(2-(2,4-dichlorophenyl)-5-isopropyloxazol-4-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl)oxy)ethan-1-ol

5.2.7. Compounds of Formula (G), (H), and (J)

In some embodiments, the compounds of the invention are compounds ofFormula (G):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹ and R⁴, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₃ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R² is hydrogen;    -   R³ is C₁₋₈ alkyl, or R³ is combined with R² to form ═O or        ═C(R⁷)(R⁸) in which each of R⁷ and R⁸ which are the same or        different, is a hydrogen or C₁₋₈ alkyl;    -   each of R⁵ and R⁶, which are the same or different, is a        hydrogen atom, C₁₋₈ alkyl, C₁₋₈ haloalkyl;    -   X and Y are the same or different and each represents CH or N;    -   Z is oxygen or sulfur;    -   A is a 5-membered heterocyclic group which is pyrazole,        thiophene, furan or pyrrole, wherein the heterocyclic group is        unsubstituted or substituted with C₁₋₈ alkyl having a        substituent which is C₁₋₈ alkyl, 3- to 7-membered cycloalkyl,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl group        substituted with a 3- to 7-membered cycloalkyl group, C₁₋₈        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, 5- or 6-membered        heterocyclic group, an aralkyl group having a C₆₋₁₀ aryl moiety        and a C₁₋₈ alkylene moiety, or 5- or 6-membered heterocyclic        group;    -   B is a C₁₋₈ alkylene chain which is unsubstituted or substituted        with C₁₋₈ alkyl, 3- to 7-membered cycloalkyl group, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl or        C₁₋₈ haloalkoxy, the alkylene group optionally having a double        bond in the case that the alkylene group has 2 to 6 carbon        atoms;    -   q is 0, 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (H):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹¹ and R¹³, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R¹² is hydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to        7-membered cycloalkyl group substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered heterocyclic group,        an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene        moiety, or a C₁₋₈ alkyl group having a 5- or 6-membered        heterocyclic substituent;    -   R¹⁴ and R¹⁵ are the same or different and each is a hydrogen        atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl;    -   X¹ is CH or N;    -   Z¹ is oxygen or sulfur;    -   W¹ is oxygen or CH₂ when bond a is present and OH when bond a is        absent;    -   q is 2, 3, or 4.    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (J):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R²¹ and R²³, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₃ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R²² is hydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to        7-membered cycloalkyl group substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered heterocyclic group,        an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene        moiety, or a C₁₋₈ alkyl group having a 5- or 6-membered        heterocyclic substituent; R²⁴ and R²⁵ are the same or different        and each is a hydrogen atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl;    -   X² is CH or N;    -   Z² is oxygen or sulfur;    -   V^(P) is oxygen or CH₂ when bond a is present and OH when bond a        is absent;    -   r is 2, 3, or 4.

R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

Regarding the Formula (G), examples of the alkyl groups having 1 to 8carbon atoms which can be R¹, R³, R⁴, R⁵, R⁶, R⁷, the substituent of the5-membered heterocyclic group for A, or the substituent of the alkylenechain having 2 to 6 carbon atoms for B include methyl, ethyl, propyl,isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl.

Examples of the alkenyl groups having 2 to 8 carbon atoms which can beR¹, R⁴, the substituent of the 5-membered heterocyclic group for A, orthe substituent of the alkylene chain having 2 to 6 carbon atoms for Binclude vinyl and allyl.

Examples of the alkynyl groups having 2 to 8 carbon atoms which can beR¹, R⁴, the substituent of the 5-membered heterocyclic group for A, orthe substituent of the alkylene chain having 2 to 6 carbon atoms for Binclude propargyl.

Examples of the 3- to 7-membered cycloalkyl groups which can be thesubstituent of the 5-membered heterocyclic group for A, or thesubstituent of the alkylene chain having 2 to 6 carbon atoms for Binclude cyclopropyl, cyclopentyl and cyclohexyl.

Examples of the alkoxy groups having 1 to 8 carbon atoms which can beR¹, R⁴, the substituent of the 5-membered heterocyclic group for A, orthe substituent of the alkylene chain having 2 to 6 carbon atoms for Binclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy,t-butoxy, pentyloxy and hexyloxy.

Examples of the halogen atoms which can be R¹, R⁴, or the substituent ofthe alkylene chain having 2 to 6 carbon atoms for B include fluorine,chlorine, and bromine.

Examples of the alkyl groups having 1 to 8 carbon atoms and a halogenatom substituent which can be R¹, R⁴, R⁵, R⁶, the substituent of the5-membered heterocyclic group for A, or the substituent of the alkylenechain having 2 to 6 carbon atoms for B include methyl, ethyl, propyl,isopropyl, butyl and t-butyl which have substituents such as 1 to 3fluorine, chlorine or bromine atoms. In some embodiments, the alkylgroup having 1 to 8 carbon atoms and a halogen atom substituent istrifluoromethyl, chloromethyl, chloroethyl, 2-bromoethyl, or2-fluoroethyl.

Examples of the alkoxy groups having 1 to 8 carbon atoms and a halogenatom substituent which can be R¹, R⁴, the substituent of the 5-memberedheterocyclic group for A, or the substituent of the alkylene chainhaving 2 to 6 carbon atoms for B include methoxy, ethoxy, propoxy,isopropyloxy, butyloxy and t-butyloxy which have substituents such as 1to 3 fluorine, chlorine or bromine atoms. In some embodiments, thealkoxy group having 1 to 8 carbon atoms and a halogen atom substituentis trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy,2-bromoethyloxy, or 2-fluoroethyloxy.

Examples of the acyl groups having 2 to 8 carbon atoms which can be R¹or R⁴, include acetyl and propionyl.

Examples of the aryl groups having 6 to 10 carbon atoms which can be R¹,R⁴, or the substituent of the 5-membered heterocyclic group for A,include phenyl.

Examples of the 5- or 6-membered heterocyclic groups which can be R¹,R⁴, or the substituent of the 5-membered heterocyclic group for A,include pyridyl.

Examples of the alkyl groups having 1 to 8 carbon atoms and a 3- to7-cycloalkyl group substituent which can be the substituent of the5-membered heterocyclic group for A, include methyl, ethyl, propyl,isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl which havecyclopropyl, cyclopentyl, or cyclophexyl substituent.

Examples of the aralkyl groups (which have an aryl moiety of 6 to 10carbon atoms and an alkylene moiety of 1 to 8 carbon atoms) which can bethe substituent of the 5-membered heterocyclic group for A, includebenzyl and phenethyl.

Examples of the alkyl groups having 1 to 8 carbon atoms and a 5- or6-membered heterocyclic group which can be the substituent of the5-membered heterocyclic group for A, include methyl, ethyl, propyl,isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl which have apyridyl substituent.

Examples of the alkyl groups having 1 to 8 carbon atoms, alkenyl groupshaving 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms,alkoxy groups having 1 to 8 carbon atoms, halogen atoms, alkyl groupshaving 1 to 8 carbon atoms and a halogen atom substituent, alkoxy groupshaving 1 to 8 carbon atoms and a halogen atom substituent, acyl groupshaving 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms, and5- or 6-membered heterocyclic groups which can be R¹¹ or R¹³ of theFormula (H) or R²¹ or R²³ of the Formula (J) are those describedhereinabove for R¹ and R⁴ of the Formula (G).

Examples of the alkyl groups having 1 to 8 carbon atoms, 3- to7-membered cycloalkyl groups, alkenyl groups having 2 to 8 carbon atoms,alkynyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8carbon atoms, alkyl groups having 1 to 8 carbon atoms and a 3- to7-membered cycloalkyl group substituent, alkyl groups having 1 to 8carbon atoms and a halogen atom substituent, alkoxy groups having 1 to 8carbon atoms and a halogen atom substituent, aryl groups having 6 to 10carbon atoms, 5- or 6-membered heterocyclic groups, aralkyl groupshaving an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of1 to 8 carbon atoms, and alkyl groups having 1 to 8 carbon atoms and a5- or 6-membered heterocyclic substituent which can be R¹² of theFormula (H) or R²² of the formula (J) include those describedhereinabove for the substituent of the 5-membered heterocyclic group forA of the Formula (G).

Examples of the alkyl groups having 1 to 8 carbon atoms and alkyl groupshaving 1 to 8 carbon atoms and a halogen atom substituent which can beR¹⁴ or R¹⁵ of the Formula (H) or R²⁴ or R²⁵ of the Formula (J) includethose described hereinabove for R⁵ and R⁶ of the Formula (G).

R¹ in the Formula (G), R¹¹ in the formula (H), and R²¹ in the formula(J) can be attached to the benzene ring or the like in a single orplural number (1 to 3). If each of R¹, R¹¹ and R²¹ is present in aplural number, the plural groups can be the same or different.

R⁴ in the Formula (G), R¹³ in the Formula (H), and R²³ in the Formula(J) can be attached to the benzene ring or the like in a single orplural number (1 to 3). If each of R⁴, R¹³ and R²³ is present in aplural number, the plural groups can be the same or different.

The substituent group of the 5-membered heterocyclic group for A in theFormula (G), R¹² in the formula (H), and R²² in the Formula (J) can beattached to the heterocyclic ring in a single or plural number (1 or 2).If each of the substituent group of the 5-membered heterocyclic groupfor A, R¹² and R²² is present in plural number, the plural groups can bethe same or different.

The compounds of the Formulas (G), (H) and (J) can be pharmacologicallyacceptable salts such as alkali metal salts, for example, sodium salts,potassium salts, or lithium salts.

The compounds of the Formulas (G), (H) and (J) can be present in theoptically active forms, and in the form of optical isomers such ascompounds of a racemic form or geometric isomers such as compounds of acis- or trans form.

In some embodiments, the compound of Formula (G), (H), or (J) is acompound shown in Table 5 or pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof.

TABLE 5 Structure Name

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl) propan-1-ol

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(3-isopropyl-5-(4-(trifluoromethyl)phenyl)thiophen-2-yl) propan-1-one

1-(4-(2-hydroxyethoxy)-3-methylphenyl)-3-(3-isopropyl-5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)propan-1-one

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)propan-1-one

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(3-isopropyl-5-(4-(trifluoromethyl)phenyl)thiophen-2-yl) propan-1-ol

1-(4-(2-hydroxyethoxy)-3-methylphenyl)-3-(3-isopropyl-5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)propan-1-ol

5.2.8. Compounds of Formula (K)

In some embodiments, the compounds of the invention are compounds ofFormula (K):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A is CH or nitrogen;    -   B, when bond a is present, is oxygen or C(R⁸)(R⁹) in which each        of R³ and R⁹ is independently hydrogen or C₁₋₈ alkyl; B, when        bond a is absent, is OH;    -   W¹ is a bond, C(═O), or (C(R¹⁰)(R¹¹))_(m) in which each of R¹⁰        and R¹¹ is independently a hydrogen or C₁₋₈ alkyl group and m is        1, 2, or 3;    -   X and Y differ from each other, and each is an oxygen atom, a        sulfur atom, a nitrogen atom, or CR¹² in which R¹² is a hydrogen        or C₁₋₈ alkyl;    -   Z¹ is a bond, oxygen, sulfur, or C(R¹³)(R¹⁴) in which each of        R¹³ and R¹⁴ is independently a hydrogen or C₁₋₈ alkyl;    -   each of R¹, R², and R³, is independently a hydrogen, C₁₋₈ alkyl,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈        haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acyl group,        C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group;    -   each of R⁴ and R⁵ is independently hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl;    -   each of R⁶ and R⁷ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, or C₁₋₈ haloalkyl    -   r is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In the Formula (K), examples of the alkyl groups having 1 to 8 carbonatoms for R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl,pentyl and hexyl.

Examples of the alkenyl groups having 2 to 8 carbon atoms for R¹, R²,R³, R⁶ and R⁷ include vinyl and allyl.

Examples of the alkynyl groups having 2 to 8 carbon atoms for R¹, R²,R³, R⁶ and R⁷ include propargyl.

Examples of the alkoxy groups having 1 to 8 carbon atoms for R¹, R², andR³ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy,t-butoxy, pentyloxy and hexyloxy.

Examples of the halogen atoms for R¹, R², and R³ include fluorine,chlorine, and bromine.

Examples of the alkyl groups having 1 to 8 carbon atoms which aresubstituted with a halogen atom for R¹, R², R³, R⁴, R⁵, R⁶, and R⁷include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which aresubstituted with 1 to 3 halogen atoms such as fluorine, chlorine, andbromine. In one embodiment, substituents are trifluoromethyl,chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-flouroethyl.

Examples of the alkoxy groups having 1 to 8 carbon atoms which aresubstituted with a halogen atom for R¹, R², and R³ include methoxy,ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy which are substitutedwith 1 to 3 halogen atoms such as fluorine, chlorine, or bromine. In oneembodiment, substituents are tritluoromethyloxy, chloromethyloxy,2-chloroethyloxy, 2-bromoethyloxy, or 2-flouroethyloxy.

Examples of the acyl groups having 2 to 8 carbon atoms for R¹, R² and R³include acetyl and propionyl.

Examples of the aryl groups having 6 to 10 carbon atoms for R¹, R² andR³ include phenyl.

Examples of the 5- or 6-membered heterocyclic groups for R¹, R² and R³include pyridyl.

R¹, R² and R³ in the Formula (K) can be attached to the benzene ring orthe like in numbers of 1 to 3 in which the same or different groups canbe attached to the same ring.

The compounds provided herein which are represented by the Formula (K)can be in the form of a pharmacologically acceptable salts such asalkali metal salts, e.g., salts of sodium, potassium and lithium.

The compounds provided herein can be in the optically active forms, andin the form of optical isomers such as compounds of a racemic form orgeometric isomers such as compounds of a cis- or trans form.

In some embodiments, the compound of Formula (K) is a compound shown inTable 6 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 6 Structure Name

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-((4-(4-isopropylphenyl)piperazin-1-yl)methyl)-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3-methylphenyl)-3-(4-((4-(4-isopropylphenyl)piperazin-1-yl)methyl)-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)propan-1-ol

5.2.9. Compounds of Formula (L)

In some embodiments, the compounds of the invention are compounds ofFormula (L):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   B, when bond a is present, is oxygen; B, when bond a is absent,        is OH;    -   W² is a bond, C(═O), or CH₂;    -   Z² is oxygen or sulfur;    -   each of R²¹, R²², and R²³ is independently a hydrogen, C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈        haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acyl group,        C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group;    -   each of R²⁴ and R²⁵ is independently hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; each R^(X6) and R^(X7) is independently H, C₁₋₆        alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In the Formula (L), the alkyl groups having 1 to 8 carbon atoms, alkenylgroups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbonatoms, alkoxy groups having 1 to 8 carbon atoms, halogen atoms, alkylgroups having 1 to 8 carbon atoms which are substituted with a halogenatom, alkoxy groups having 1 to 8 carbon atoms which are substitutedwith a halogen atom, hydroxyls, nitros, acyl groups having 2 to 8 carbonatoms, aryl groups having 6 to 10 carbon atoms, and 5- or 6-memberedheterocyclic groups for R²¹, R²² and R²³ can in some embodiments bethose described for R¹, R² and R³ in the Formula (K).

In the Formula (L), the alkyl groups having 1 to 8 carbon atoms andalkyl groups having 1 to 8 carbon atoms which are substituted with ahalogen atom for R²⁴ and R²⁵ can in some embodiments be those describedfor R⁴ and R⁵ in the Formula (K).

R²¹, R²² and R²³ in the Formula (L) can be attached to the benzene ringor the like in numbers of 1 to 3 in which the same or different groupscan be attached to the same ring.

The compounds provided herein which are represented by the Formula (L)can be in the form of a pharmacologically acceptable salts such asalkali metal salts, e.g., salts of sodium, potassium and lithium.

The compounds provided herein can be in the optically active forms, andin the form of optical isomers such as compounds of a racemic form orgeometric isomers such as compounds of a cis- or trans form.

5.2.10. Compounds of Formula (M) and (N)

In In some embodiments, the compounds of the invention are compounds ofFormula (M):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein: each of W¹ and W² is independently        nitrogen or CH;    -   X is nitrogen or CH;    -   Y is oxygen or sulfur;    -   Z is a bond, oxygen, sulfur or NR⁵, in which R⁵ is hydrogen or        C₁₋₈ alkyl;    -   each of R¹ and R² is independently hydrogen, halogen, hydroxyl,        nitro, amino, C₁₋₈ alkyl, 3- to 7-membered cycloalkyl group,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3-        to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, 5- or 6-membered heterocyclic group, an        aralkyl group having C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene, or        C₁₋₈ alkyl having a 5- or 6-membered heterocyclic substituent;    -   each of R³ and R⁴ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈        haloalkyl;    -   A is a 5-membered heterocycle which is pyrazole, thiophene,        furan, isoxazole, isothiazole or pyrrole, in which the        5-membered heterocycle is unsubstituted or substituted with        halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl, 3- to 7-membered        cycloalkyl group, C₂₋₈ alkenyl, C₂₋₃ alkynyl, C₁₋₈ alkoxy, C₁₋₈        alkyl having a 3- to 7-membered cycloalkyl substituent, C₁₋₈        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered        heterocyclic group, an aralkyl group having a C₆₋₁₀ aryl moiety        and C₁₋₈ alkylene moiety, or C₁₋₈ alkyl group having a 5- or        6-membered heterocyclic substituent;    -   B is a bond or C₁₋₈ alkylene which is unsubstituted or        substituted with C₁₋₈ alkyl, 3- to 7-membered cycloalkyl, C₁₋₈        alkoxy or a halogen substituent, optionally wherein the C₁₋₈        alkylene has a double or triple bond;    -   r is 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H, 3

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (N):

-   -   a or a pharmaceutically acceptable salt, solvate, ester, amide,        or prodrug thereof, wherein:    -   W³ is nitrogen or CH;    -   Z¹ is oxygen or sulfur;    -   each of R¹¹ and R¹² is independently hydrogen, halogen,        hydroxyl, nitro, amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl,        or C₁₋₈ haloalkoxy′    -   each of R¹³ and R¹⁴ is independently hydrogen or C₁₋₈ alkyl;    -   A¹ is a 5-membered heterocycle which is pyrazole or thiophene,        in which the 5-membered heterocycle is unsubstituted or        substituted with halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl,        C₁₋₈ alkoxy, C₁₋₈ haloalkyl, or C₁₋₈ haloalkoxy;    -   m is 2, 3, or 4;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments of compounds of Formula (M), the alkyl group having1 to 8 carbon atoms for R¹, R², R³, R⁴, R⁵, a substituent attached tothe 5-membered hetero ring of A (when present), and a substituentattached to an alkylene chain having 1 to 8 carbon atoms can be methyl,ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, or hexyl.

In one embodiment, the alkenyl group having 2 to 8 carbon atoms for R¹,R² and a substituent is attached to the 5-membered hetero ring of A andis vinyl or allyl.

In one embodiment, the alkyny 1 group having 2 to 8 carbon atoms for R¹,R², wherein a substituent is attached to the 5-membered hetero ring of Aand is propargyl.

In one embodiment, the 3- to 7-membered cycloalkyl group for R¹, R²,wherein a substituent is attached to the 5-membered hetero ring of A. Inanother embodiment, a substituent is attached to the alkylene chainhaving 1 to 8 carbon atoms and is cyclopentyl or cyclohexyl.

In one embodiment, the alkoxy group having 1 to 8 carbon atoms for R¹,R², wherein a substituent is attached to the 5-membered hetero ring ofA. In another embodiment, a substituent is attached to the alkylenechain having 1 to 8 carbon atoms and is methoxy, ethoxy, propoxy,isopropoxy, butoxy, i-butoxy, t-butoxy, pentyloxy, or hexyloxy.

In one embodiment, R¹ and R² is halogen, a substituent is attached tothe 5-membered hetero ring of A. In another embodiment, a substituent isattached to the alkylene chain having 1 to 8 carbon atoms and isfluorine, chlorine, or bromine.

In one embodiment, the alkyl group having 1 to 8 carbon atoms and ahalogen substituent for R¹, R², R⁵, wherein a substituent is attached tothe 5-membered hetero ring of A and is methyl, ethyl, propyl, isopropyl,butyl or t-butyl which has 1 to 3 halogen substituents such as fluorine,chlorine or bromine. In another embodiment, the substituents areselected from trifluoromethyl, chloromethyl, 2-chloroethyl,2-bromoethyl, and 2-fluoroethyl.

In one embodiment, the alkoxy group having 1 to 8 carbon atoms and ahalogen substituent for R¹, R², wherein a substituent is attached to the5-membered hetero ring of A and is methoxy, ethoxy, propoxy, isopropoxy,butyloxy or t-butyloxy which has 1 to 3 halogen substituents such asfluorine, chlorine or bromine. In one embodiment, the substituents areselected from trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy,2-bromoethyloxy, and 2-fluoroethyloxy.

In one embodiment, the aryl group having 6 to 10 carbon atoms for R¹,R², and a substituent is attached to the 5-membered hetero ring of A andis phenyl.

In one embodiment, the 5- or 6-membered heterocyclic group for R¹, R²,and a substituent is attached to the 5-membered hetero ring of A and ispyridyl.

In one embodiment, the alkyl group having 1 to 8 carbon atoms and 3- to7-membered cycloalkyl group for R¹, R², and a substituent is attached tothe 5-membered hetero ring of A and is methyl, ethyl, propyl, isopropyl,butyl, i-butyl, t-butyl, pentyl, or hexyl which has a cyclopropylsubstituent, a cyclopentyl substituent, or a cyclohexyl substituent.

In one embodiment, the aralkyl having an aryl moiety of 6 to 10 carbonatoms and an alkylene moiety of 1 to 8 carbon atoms for R¹, R², and asubstituent is attached to the 5-membered hetero ring of A and is benzylor phenethyl.

In one embodiment, the alkyl group having 1 to 8 carbon atoms and 5- or6-membered heterocyclic group for R¹, R², and a substituent is attachedto the 5-memberedhetero ring of A and is methyl, ethyl, propyl,isopropyl, butyl, i-butyl, t-butyl, pentyl, or hexyl which has a pyridylsubstituent.

In one embodiment, the 5-membered hetero ring, which may have asubstituent for A, is pyrazole or thiophene having a substituent. Inanother embodiment, pyrazole is having a substituent.

In one embodiment, the alkylene chain having 1 to 8 carbon atoms whichhas substituent for B is an alkylene chain having 1 to 4 carbon atoms.In another embodiment, the alkylene chain is an ethylene chain or apropylene chain.

In one embodiment, n is 0.

In some embodiment of the compounds of Formula (N), the halogen atom,alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8carbon atoms, alkyl group having 1 to 8 carbon atoms and a halogensubstituent, and alkoxy group having 1 to 8 carbon atoms and a halogensubstituent for R¹¹ and R¹² can be those described hereinbefore for R¹and R² of the Formula (M).

In one embodiment, the alkyl group having 1 to 8 carbon atoms for R¹³and R¹⁴ can be those described hereinbefore for R³ and R⁴ of the Formula(M).

In one embodiment, the halogen atom, alkyl group having 1 to 8 carbonatoms, alkoxy group having 1 to 8 carbon atoms, alkyl group having 1 to8 carbon atoms and a halogen substituent, and alkoxy group having 1 to 8carbon atoms and a halogen substituent which is attached to pyrazole orthiophene for A¹ in the Formula (N) are those described hereinbefore forthe substituents attached to the 5-membered hetero ring of A of theFormula (M).

In one embodiment, R¹ of the Formula (M) and R¹¹ of the Formula (N), thebenzene ring or the like can have 1 to 3 number of R¹ or R¹¹ which arethe same or different from each other. In another embodiment, thebenzene ring or the like can have 1 to 3 substituents other than ahydrogen atom.

In one embodiment, R² of the Formula (M) and R¹² of the Formula (N), thebenzene ring of the benzisoxazole ring or the like can have 1 to 3number of R² or R¹² which are the same or different from each other. Inanother embodiment, the benzene ring of the benzisoxazole ring or thelike can have 1 to 3 substituents other than a hydrogen atom.

In one embodiment, the substituent attached to the 5-membered heteroring for A of the Formula (M) and the substituent attached to pyrazoleor thiophene for A¹ of the Formula (N) can be present in 1 or 2 numberwhich can be the same or different from each other.

The compounds provided herein which are represented by the Formula (M)and (N) can be in the form of a pharmacologically acceptable salts suchas alkali metal salts, e.g., salts of sodium, potassium and lithium.

The compounds provided herein can be in the optically active forms, andin the form of optical isomers such as compounds of a racemic form orgeometric isomers such as compounds of a cis- or trans form.

In some embodiments, the compound of Formula (M) or (N) is a compoundshown in Table 7 or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof.

TABLE 7 Structure Name

2-((3-(2-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl)oxy)-2-methylpropan-1-ol

2-((3-(2-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl) oxy)ethan-1-ol

5.2.11. Compounds of Formula (O), (P) and (Q)

In some embodiments, the compounds of the invention are compounds ofFormula (O):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of W¹ and W² independently is CH or nitrogen;    -   X is NR⁵ or CR⁶R⁷; wherein R⁵ is hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl, C₁₋₈ alkyl substituted with C₁₋₈ alkoxy, C₃₋₇        cycloalkyl, C₁₋₈ alkyl substituted with C₃₋₇ cycloalkyl, C₁₋₈        alkyl substituted with phenyl, C₂₋₈ acyl, or C₂₋₈ alkenyl, and        each of R⁶ and R⁷ independently is hydrogen or C₁₋₈ alkyl;    -   Y is (CR⁸R⁹)_(r), wherein each of R³ and R⁹ independently is        hydrogen or C₁₋₈ alkyl, and r is 1, 2, 3, or 4; or    -   X and Y are combined to form CR¹⁰═CR¹¹ or ethynylene, wherein        each of R¹⁰ and R¹¹ independently is hydrogen or C₁₋₈ alkyl;    -   G, when bond a is present, is 0, S or CR¹²R¹³, wherein each of        R¹² and R¹³ independently is hydrogen or C₁₋₈ alkyl; G, when        bond a is absent, is OH;    -   A is a five-membered heterocyclic ring which is thiazole,        oxazole, imidazole, pyrazole, thiophene, furan, or pyrrole,        wherein the heterocyclic ring is unsubstituted or substituted        with C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl, nitro, C₂₋₈        acyl, C₆₋₁₀ aryl, or a five-membered or six-membered        heterocyclic group;    -   B is a C₁₋₈ alkylene, C₂₋₈ alkenylene or C₂₋₈ alkynylene chain,        wherein the chain is unsubstituted or substituted with C₁₋₈        alkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, or halogen;    -   each of R¹ and R² independently is hydrogen, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl,        C₁₋₈ haloalkoxy, hydroxyl, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a        five-membered or six-membered heterocyclic group;    -   each of R³ and R⁴ independently is hydrogen or C₁₋₈ alkyl;    -   m is 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (P):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   G^(a), when bond a is present, is 0, S or CH₂; G^(a), when bond        a is absent, is OH.    -   A^(a) is five-membered heterocyclic ring which is thiazole,        oxazole, or thiophene, wherein the five-membered heterocyclic        ring is unsubstituted or is substituted with C₁₋₈ alkyl, C₁₋₈        alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   B^(a) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain;    -   each of R^(1a) and R^(2a) independently is hydrogen, C₁₋₈ alkyl,        C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (Q):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   G^(b), when bond a is present, is O, S or CH₂; G^(b), when bond        a is absent, is OH;    -   A^(b) is five-membered heterocyclic ring which is thiazole,        oxazole, or thiophene, wherein the five-membered heterocyclic        ring is unsubstituted or is substituted with C₁₋₈ alkyl, C₁₋₈        alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   B^(b) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain;    -   each of R^(1b) and R^(2b) independently is hydrogen, C₁₋₈ alkyl,        C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   R^(3b) is hydrogen or C₁₋₈ alkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, in the Formula (O), R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R, R¹², R¹³, a substituent of the five-membered heterocyclicring represented by A, and a substituent of the C₁₋₈ alkylene, C₂₋₈alkenylene or C₂₋₈ alkynylene chain represented by B can be C₁₋₈ alkyl.Examples of the C₁₋₈ alkyl include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl and hexyl.

In one embodiment, R¹, R², R⁵, and a substituent of the five-memberedheterocyclic ring represented by A can be C₂₋₈ alkenyl. Examples of theC₂₋₈ alkenyl include vinyl and allyl.

In one embodiment, R¹, R², and a substituent of the five-memberedheterocyclic ring represented by A can be C₂₋₈ alkynyl. Examples of theC₂₋₈ alkynyl include propargyl.

In one embodiment, R¹, R², a substituent of the five-memberedheterocyclic ring represented by A, and a substituent of the C₁₋₈alkylene, C₂₋₈ alkenylene or C₂₋₈ alkynylene chain represented by B canbe C₁₋₈ alkoxy. Examples of the C₁₋₈ alkoxy in-clude methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, andhexyloxy.

In one embodiment, R¹, R², a substituent of the five-memberedheterocyclic ring represented by A, and a substituent of the C₁₋₈alkylene, C₂₋₈ alkenylene or C₂₋₈ alkynylene chain represented by B canbe halogen. Examples of the halogen include fluorine, chlorine, andbromine.

In one embodiment, R¹, R², R⁵, and a substituent of the five-memberedheterocyclic ring represented by A can be C₁₋₈ alkyl substituted withhalogen. Examples of the C₁₋₈ alkyl substituted with halogen includemethyl, ethyl, propyl, isopropyl, butyl, and t-butyl which aresubstituted with 1-3 halogens such as fluorine, chlorine, and bromine.Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl,2-bromoethyl, and 2-fluoroethyl.

In one embodiment, R¹, R², and a substituent of the five-memberedheterocyclic ring represented by A can be C₁₋₈ alkoxy substituted withhalogen.

Examples of the C₁₋₈ alkoxy substituted with halogen include methoxy,ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy which are substitutedwith 1-3 halogen atoms such as fluorine atom, chlorine atom, or bromineatom. In one embodiment, R¹, R², and a substituent of the five-memberedheterocyclic ring are trifluoromethoxy, chloromethoxy, 2-chloroethoxy,2-bromoethoxy, and 2-fluoroethoxy.

In one embodiment, R¹, R², R⁵, and a substituent of the five-memberedheterocyclic ring represented by A can be C₂₋₈ acyl. Examples of theC₂₋₈ acyl include acetyl and propionyl.

In one embodiment, R¹, R², and a substituent of the five-memberedheterocyclic ring represented by A can be C{circumflex over ( )}.\Qaryl. Examples of the C₆₋₁₀ aryl include phenyl.

In one embodiment, R¹, R², and a substituent of the five-memberedheterocyclic ring represented by A can be a five-membered orsix-membered heterocyclic group. Examples of the five-membered orsix-membered heterocyclic group include pyridyl.

In one embodiment, R⁵ can be C₁₋₈ alkyl substituted with C₁₋₈ alkoxy.

Examples of the C₁₋₈ alkyl substituted with C₁₋₈alkoxy include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexylwhich are substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, t-butoxy, pentyloxy, or hexyloxy.

In one embodiment, R⁵ can be cycloalkyl of three-membered toseven-membered ring. Examples of the cycloalkyl of three-membered toseven-membered ring include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

In one embodiment, R⁵ can be C₁₋₈ alkyl substituted with cycloalkyl ofthree-membered to seven-membered ring. Examples of the C₁₋₈ alkylsubstituted with cycloalkyl of three-membered to seven-membered ringinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl and hexyl which are substituted with cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

In one embodiment, R⁵ can be C₁₋₈ alkyl substituted with phenyl.

Examples of the C₁₋₈ alkyl substituted with phenyl include benzyl andphenethyl.

In one embodiment, a substituent of the C₁₋₈ alkylene, C₂₋₈ alkenyleneor C₂₋₈ alkynylene chain represented by B can be cycloalkyl ofthree-membered to seven-membered ring. Examples of the cycloalkyl ofthree-membered to seven-membered ring include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In some embodiments, in the Formula (P), R^(1a), R^(2a), and asubstituent of five-membered heterocyclic ring represented by A^(a) canbe C₁₋₈ alkyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted withhalogen, C₁₋₈ alkoxy substituted with halogen, and C₂₋₈ acyl. Examplesof them are the same as the examples of R¹, R², and the substituent ofthe five-membered heterocyclic ring represented by A in the Formula (O).

In some embodiments, in the Formula (Q), R^(1b), R^(2b), and asubstituent of five-membered heterocyclic ring represented by A^(b) canbe C₁₋₈ alkyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted withhalogen, C₁₋₈ alkoxy substituted with halogen, and C₂₋₈ acyl. Examplesof them are the same as the examples of R¹, R², and the substituent ofthe five-membered heterocyclic ring represented by A in the Formula (O).

In one embodiment, in the Formula (Q), R^(3b) can be C₁₋₈ alkyl.Examples are the same as the examples of R⁵ in the Formula (O).

In one embodiment, each of R¹, R² in the Formula (O), R^(1a), R^(2a) inthe Formula (P), R^(1b) and R^(2b) in the Formula (Q) can be one tothree groups attached to the rings, such as benzene ring. The two orthree groups can be different from each other.

The compounds having the Formulae (O), (P), and (Q) can be present inthe form of a pharmaceutically acceptable salt. Examples of the saltinclude an alkali metal salt, such as sodium salt, potassium salt andlithium salt.

The compounds having the Formulae (O), (P), and (Q) can also be presentin the form of an optical isomer such as enantiomer or racemic body, ora geometrical isomer such as cis or trans. Also provided are isomers ofthese compounds.

In some embodiments, the compound of Formula (O), (P), or (Q) is acompound shown in Table 8 or pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof.

TABLE 8 Structure Name

1-(4-(3-hydroxypropyl)-3-methylphenyl)-3-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)propan-1-one

1-(4-((2-hydroxyethyl) (methyl)amino)phenyl)-3-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol- 5-yl)propan-1-one

5.2.12. Compounds of Formula (R) and (S)

In some embodiments, the compounds of the invention are compounds ofFormula (R):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of W¹ and W² is independently CH or N;    -   X is NR³ or CR⁴R⁵, in which R³ is C₁₋₈ alkyl, C₁₋₈ haloalkyl,        C₁₋₈ alkyl substituted with C₁₋₈ alkoxy, C₁₋₈ alkyl substituted        with a 3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with a        phenyl group, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   each of R⁴ and R⁵ is independently hydrogen or C₁₋₈ alkyl;    -   Y is (CR⁶R⁷)_(r), in which each of R⁶ and R⁷ is independently        hydrogen or C₁₋₈ alkyl and r is 1, 2, 3, or 4;    -   A is a 5 or 6-membered heterocyclic group which is thiazole,        oxazole, imidazole, pyrazole, thiophene, furan, pyrrole,        pyridine or pyrimidine, or a phenyl group, wherein the 5 or        6-membered heterocyclic group or phenyl group is unsubstituted        or substituted with C₁₋₈ alkyl, 3-7 membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxyl, C₁₋₈ alkyl group        substituted with a 3-7 membered cycloalkyl group, C₁₋₈        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5 or 6-membered        heterocyclic group, aralkyl group comprising a C₆₋₁₀ aryl group        and a C₁₋₈ alkyl group, or C₁₋₈ alkyl group substituted with a 5        or 6-membered heterocyclic group;    -   B is a bond or C₁₋₈ alkylene which is unsubstituted or        substituted with C₁₋₈ alkyl, a 3-7 membered cycloalkyl group,        C₁₋₈ alkoxy or a halogen, and which may have a double bond or        triple bond when the carbon number of the alkylene chain is 2 or        more;    -   D is N or CH;    -   E is O or S;    -   each of R¹ and R² is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a 5 or 6-membered        heterocyclic group;    -   m 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention are compounds ofFormula (S):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A¹ is a 5 or 6-membered heterocyclic group which is thiazole,        oxazole, pyridine or pyrimidine, or a phenyl group, wherein the        5 or 6-membered heterocyclic group or phenyl group is        unsubstituted or substituted with C₁₋₈ alkyl or C₁₋₈ haloalkyl;    -   B¹ is C₂₋₄ alkylene;    -   each of R¹¹ and R¹² is independently H, C₁₋₈ alkyl, halogen, or        C₁₋₈ haloalkyl;    -   R¹³ is C₁₋₈ alkyl or C₁₋₈ haloalkyl, optionally wherein the N to        which R¹³ is attached is attached to the 6th position of        benzisoxazole;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, of the compounds having the Formula (R), both W¹and W² are CH.

In some embodiments of the compounds having the Formula (R), X is CR⁴R⁵,CH₂, or NR³, and R³ is an alkyl group having 1 to 8 carbon atoms. Inanother embodiment, R³ is a methyl group.

In some embodiments of the compounds having the Formula (R), Y is CH₂.

In some embodiments of the compounds having the Formula (R), Z is acarboxylic group.

In some embodiments of the compounds, having the Formula (R), A isthiazole or oxazole which may have a substituent selected from the groupconsisting of an alkyl group having 1 to 8 carbon atoms, an alkenylgroup having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and a halogen atomsubstituent, an aryl group having 6 to 10 carbon atoms or a 5 or6-membered heterocyclic group; pyrazole which may have a substituentselected from the group consisting of an alkyl group having 1 to 8carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynylgroup having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbonatoms and a halogen atom substituent, an aryl group having 6 to 10carbon atoms or a 5 or 6-membered heterocyclic group.

In some embodiments of the compounds having the Formula (R), B is anethylene chain.

In some embodiments of the compounds having the Formula (R), D is N.

In some embodiments of the compounds having the Formula (R), E is O.

In some embodiments of the compounds having the Formula (R), each of R¹and R² is independently H, an alkyl group having 1 to 8 carbon atoms, analkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atomsand a halogen atom substituent or an alkoxy group having 1 to 8 carbonatoms and a halogen atom substituent.

In some embodiments of the compounds having the Formula (R), m is 0.

In some embodiments of the compounds having the Formula (S), R¹³ is analkyl group having 1 to 8 carbon atoms. In another embodiment, R¹³ is amethyl group.

In some embodiments of the compounds having the Formula (S), p is 1.

In some embodiments of the compounds having the Formula (S), A¹ isthiazole, oxazole or phenyl which may have a substituent selected fromthe group consisting of an alkyl group having 1 to 8 carbon atoms or analkyl group having 1 to 8 carbon atoms and a halogen atom substituent.In another embodiment, A¹ is thiazole which may have an alkyl grouphaving 1 to 8 carbon atoms as a substituent.

In some embodiments of the compounds having the Formula (S), B¹ is anethylene chain.

In some embodiments of the compounds having the Formula (S), R¹¹ is analkyl group having 1 to 8 carbon atoms, a halogen atom or an alkyl grouphaving 1 to 8 carbon atoms and a halogen atom substituent.

In some embodiments of the compounds having the Formula (S), R¹² is H,an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to8 carbon atoms and a halogen atom substituent.

The compounds having the Formulae (R) and (S) can also be present in theform of an optical isomer such as enantiomer or racemic body, or ageometrical isomer such as cis or trans. Also provided are isomers ofthese compounds.

The compounds having the Formulae (R) and (S) can be present in the formof a pharmaceutically acceptable salt. Examples of the salt include analkali metal salt, such as sodium salt, potassium salt and lithium salt.

In some embodiments, the compound of Formula (R) or (S) is a compoundshown in Table 9 or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof.

TABLE 9 Structure Name

2-((3-(2-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethyl)benzo[d]isoxazol-6-yl)(methyl) amino)ethan-1-ol

2-((3-(2-(4-isopropyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethyl)-5-methylbenzo[d]isoxazol-6-yl)(methyl)amino)ethan-1-ol

5.2.13. Compounds of Formula (T)

In some embodiments, the compounds of the invention are compounds ofFormula (T):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   B² is C₂₋₄ alkylene;    -   R²⁰ is C₁₋₈ alkyl;    -   each of R²¹ and R²² is independently H, C₁₋₈ alkyl, halogen, or        C₁₋₈ haloalkyl;    -   R²³ is C₁₋₈ alkyl or C₁₋₈ haloalkyl, optionally wherein the N to        which R²³ is attached is attached to the 6th position of        benzisoxazole;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, R²³ is an alkyl group having 1 to 8 carbon atoms oran alkyl group having 1 to 8 carbon atoms and a halogen atomsubstituent. In another embodiment, R²³ is a methyl group.

In some embodiments, n is an integer of 1 to 4. In some embodiments, nis 1.

In some embodiments, R²⁰ is an alkyl group having 1 to 8 carbon atoms.In another embodiment, R²⁰ is methyl.

In some embodiments, B² is an alkylene chain having 2 to 4 carbon atoms.In another embodiment, B² is an ethylene chain.

In some embodiments, each of R²¹ and R²² is independently H, an alkylgroup having 1 to 8 carbon atoms, a halogen atom, an alkyl group having1 to 8 carbon atoms and a halogen atom substituent. In anotherembodiment, R²¹ is an alkyl group having 1 to 8 carbon atoms, a halogenatom or an alkyl group having 1 to 8 carbon atoms and a halogen atomsubstituent. In yet another embodiment, R²² is H, an alkyl group having1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and ahalogen atom substituent.

In some embodiments, N(R²³)((CH₂)_(n)—R^(x)) is attached to the 6thposition of benzisoxazole.

The compounds having the Formula (T) can also be present in the form ofan optical isomer such as enantiomer or racemic body, or a geometricalisomer such as cis or trans. Also provided are isomers of thesecompounds.

The compounds having the Formula (T) can be present in the form of apharmaceutically acceptable salt. Examples of the salt include an alkalimetal salt, such as sodium salt, potassium salt and lithium salt.

5.2.14. Compounds of Formula (U)

In some embodiments, the compounds of the invention are compounds ofFormula (U):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R² is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ alkyl having a 3-        to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl        group having a C₁₋₈ alkoxy substituent, C₂₋₈ acyl, C₆₋₁₀ aryl,        or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R³, R⁴, R⁵ and R⁶ independently is hydrogen, C₁₋₈ alkyl,        or C₁₋₈ haloalkyl;    -   X is oxygen, sulfur or NR⁷; where R⁷ is hydrogen, C₁₋₈ alkyl,        C₁₋₈ haloalkyl, an aralkyl group having a C₆₋₁₀ aryl moiety and        a C₁₋₈ alkylene moiety, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   Y is oxygen, sulfur, NR⁸ or a bond, where R^(a) is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   p is 0 or 1;    -   A, when bond a is present, is oxygen CH₂, N—NH₂ or N—OR⁹, where        R⁹ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, C₂₋₈        alkenyl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a        C₁₋₈ alkylene moiety; A, when bond a is absent, is OH;    -   B is, in the case of p=1, a benzene ring having or not having a        substituent which is halogen, hydroxyl, nitro, amino, C₁₋₈        alkyl, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, or an aralkyl        group having a C₆₋₁₀ aryl moiety and a C1-C8 alkylene moiety of        1-8 carbon atoms, and, in the case of p=0, a condensed ring        which is indole, benzofuran, benzisoxazole or        1,2-benzisothiazole, in which said condensed ring has or does        not have a substituent which is    -   halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl group, C₃₋₇        cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₃ alkoxy, C₁₋₈ alkyl        having a 3- to 7-membered cycloalkyl substituent, C₁₋₈        haloalkyl, C₁₋₈ alkyl having a C1-C8 alkoxy substituent, C₁₋₈        haloalkoxy group, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   Y is bonded to the benzene ring of B;    -   (C(R³)(R⁴))_(m) is bonded to the condensed ring of B at its        3-position;    -   m is an integer of 1 to 4;    -   n is 0, 1, 2, 3, 4, or 5;    -   Y is a bond in the case of n=0;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

In some embodiments, R¹ represents hydrogen, halogen, hydroxyl, nitro,amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms,an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to7-membered cycloalkyl substituent, an alkyl group having 1-8 carbonatoms and having a halogen substituent, an alkyl group having 1-8 carbonatoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy grouphaving 1-8 carbon atoms and having a halogen substituent, an acyl grouphaving 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or6-membered heterocyclic group, an aralkyl group having an aryl moiety of6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms, or analkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclicsubstituent.

In some embodiments, R² represents hydrogen, an alkyl group having 1-8carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl grouphaving 1-8 carbon atoms and having a 3- to 7-membered cycloalkylsubstituent, an alkyl group having 1-8 carbon atoms and having a halogensubstituent, an alkyl group having 1-8 carbon atoms and having an alkoxysubstituent having 1-8 carbon atoms, an acyl group having 2-8 carbonatoms, an aryl group having 6-10 carbon atoms, or an aralkyl grouphaving an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8carbon atoms.

In some embodiments, each of R³, R⁴, R⁵ and R⁶ independently representshydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl grouphaving 1-8 carbon atoms and having a halogen substituent.

In some embodiments, X is oxygen, sulfur or NR⁷, R⁷ representinghydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having1-8 carbon atoms and having a halogen substituent, an aralkyl grouphaving an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8carbon atoms, an acyl group having 2-8 carbon atoms, or an alkenyl grouphaving 2-8 carbon atoms.

In some embodiments, Y is oxygen, sulfur, NR or a bond, R⁸ representinghydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having1-8 carbon atoms and having a halogen substituent, an acyl group having2-8 carbon atoms, or an alkenyl group having 2-8 carbon atoms.

In some embodiments, p is 0 or 1.

In some embodiments, A is oxygen, CH₂, N—NH₂ or N—OR⁹, R⁹ representinghydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having1-8 carbon atoms and having a halogen substituent, an acyl group having2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or anaralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylenemoiety of 1-8 carbon atoms.

In some embodiments, B represents, in the case of p=1, a benzene ringhaving or not having a substituent selected from the group consisting ofhalogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms,3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbonatoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3-to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbonatoms and having a halogen substituent, an alkyl group having 1-8 carbonatoms and having an alkoxy substituent having 1-8 carbon atoms, analkoxy group having 1-8 carbon atoms and having a halogen substituent,an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbonatoms, or an aralkyl group having an aryl moiety of 6-10 carbon atomsand an alkylene moiety of 1-8 carbon atoms, and, in the case of p=0, acondensed ring selected from the group consisting of indole, benzofuran,benz-isoxazole and 1,2-benzisothiazole, in which said condensed ring hasor does not have a substituent selected from the group consisting ofhalogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms,3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbonatoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3-to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbonatoms and having a halogen substituent, an alkyl group having 1-8 carbonatoms and having an alkoxy sub-stituent having 1-8 carbon atoms, analkoxy group having 1-8 carbon atoms and having a halogen substituent,an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbonatoms, or an aralkyl group having an aryl moiety of 6-10 carbon atomsand an alkylene moiety of 1-8 carbon atoms.

In some embodiments, Y is bonded to the benzene ring of B.

In some embodiments, —(C(R³)(R⁴))_(m)— is bonded to the condensed ringof B at its 3-position.

In some embodiments, m is an integer of 1 to 4.

In some embodiments, n is an integer of 0 to 5.

In some embodiments, Y is a bond in the case of n=0.

The compounds having the Formula (U) can also be present in the form ofan optical isomer such as enantiomer or racemic body, or a geometricalisomer such as cis or trans. Also provided are isomers of thesecompounds.

The compounds having the Formula (U) can be present in the form of apharmaceutically acceptable salt. Examples of the salt include an alkalimetal salt, such as sodium salt, potassium salt and lithium salt.

5.2.15. Compounds of Formula (V)

In some embodiments, the compounds of the invention are compounds ofFormula (V):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R¹² is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ alkyl having a        3- to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈ acyl, C₁₋₁₀        aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R¹³, R¹⁴, R¹⁵ and R¹⁶ independently is hydrogen, C₁₋₈        alkyl, or C₁₋₈ haloalkyl;    -   Y¹ is oxygen, sulfur, NR¹⁸ or a bond, where R¹⁸ is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   A¹, when bond a is present, is oxygen CH₂, N—NH₂ or N—OR¹⁹,        where R¹⁹ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl,        C₂₋₈ alkenyl, or an aralkyl group having a C₆₋₁₀ aryl moiety and        a C₁₋₈ alkylene moiety; A¹, when bond a is absent, is OH;    -   Q¹ is hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl        group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₃ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   r is 1, 2, 3, or 4;    -   s is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

In some embodiments, R¹¹ represents hydrogen, halogen, hydroxyl, nitro,amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms,an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to7-membered cycloalkyl substituent, an alkyl group having 1-8 carbonatoms and having a halogen substituent, an alkyl group having 1-8 carbonatoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy grouphaving 1-8 carbon atoms and having a halogen substituent, an acyl grouphaving 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or6-membered heterocyclic group, an aralkyl group having an aryl moiety of6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms, or analkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclicsubstituent.

In some embodiments, R¹² represents hydrogen, an alkyl group having 1-8carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl grouphaving 1-8 carbon atoms and having a 3- to 7-membered cycloalkylsubstituent, an alkyl group having 1-8 carbon atoms and having a halogensubstituent, an alkyl group having 1-8 carbon atoms and having an alkoxysubstituent having 1-8 carbon atoms, an acyl group having 2-8 carbonatoms, an aryl group having 6-10 carbon atoms, or an aralkyl grouphaving an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8carbon atoms.

In some embodiments, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ independentlyrepresents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkylgroup having 1-8 carbon atoms and having a halogen substituent.

In some embodiments, Y¹ is oxygen, sulfur, NR¹⁸ or a bond, R¹⁸representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkylgroup having 1-8 carbon atoms and having a halogen substituent, an acylgroup having 2-8 carbon atoms, or an alkenyl group having 2-8 carbonatoms.

In some embodiments, A¹ is oxygen CH₂, N—NH₂ or N—OR¹⁹, R¹⁹ representinghydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having1-8 carbon atoms and having a halogen substituent, an acyl group having2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or anaralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylenemoiety of 1-8 carbon atoms.

In some embodiments, Q¹ represents hydrogen, halogen, hydroxyl, nitro,amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-memberedcycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynylgroup having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms,an alkyl group having 1-8 carbon atoms and having a 3- to 7-memberedcycloalkyl substituent, an alkyl group having 1-8 carbon atoms andhaving a halogen substituent, an alkyl group having 1-8 carbon atoms andan alkoxy substituent having 1-8 carbon atoms, an alkoxy group having1-8 carbon atoms and having a halogen substituent, an acyl group having2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkylgroup having an aryl moiety of 6-10 carbon atoms and an alkylene moietyof 1-8 carbon atoms.

In some embodiments, r is an integer of 1 to 4.

In some embodiments, s is an integer of 1 to 5.

The compounds having the Formula (V) can also be present in the form ofan optical isomer such as enantiomer or racemic body, or a geometricalisomer such as cis or trans. Also provided are isomers of thesecompounds.

The compounds having the Formula (V) can be present in the form of apharmaceutically acceptable salt. Examples of the salt include an alkalimetal salt, such as sodium salt, potassium salt and lithium salt.

In some embodiments, the compound of Formula (V) is a compound shown inTable 10 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 10 Structure Name

1-(4-(3-hydroxypropyl)-3- methylphenyl)-3-(3-isopropyl-6-(trifluoromethyl)benzo[b]thiophen- 2-yl)propan-1-one

1-(4-(3-hydroxypropyl)-3- methylphenyl)-3-(3-isopropyl-6-(trifluoromethyl)benzo[b]thiophen- 2-yl)propan-1-ol

5.2.16. Compounds of Formula (W)

In some embodiments, the compounds of the invention are compounds ofFormula (A):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R²² is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ alkyl having a        3- to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈ acyl, C₆₋₁₀        aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R²³, R²⁴, R²⁵ and R²⁶ independently is hydrogen, C₁₋₈        alkyl, or C₁₋₈ haloalkyl;    -   Y² is oxygen, sulfur, NR²⁸ or a bond, where R²⁸ is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   Q² is hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl        group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   t is 1, 2, 3, or 4;    -   u is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH COH COOCH₂CONR^(X4)R^(X5) SO₃H

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

In some embodiments, R²¹ represents hydrogen, halogen, hydroxyl, nitro,amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms,an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to7-membered cycloalkyl substituent, an alkyl group having 1-8 carbonatoms and having a halogen substituent, an alkyl group having 1-8 carbonatoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy grouphaving 1-8 carbon atoms and having a halogen substituent, an acyl grouphaving 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or6-membered heterocyclic group, an aralkyl group having an aryl moiety of6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms, or analkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclicsubstituent.

In some embodiments, R²² represents hydrogen, an alkyl group having 1-8carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl grouphaving 1-8 carbon atoms and having a 3- to 7-membered cycloalkylsubstituent, an alkyl group having 1-8 carbon atoms and having a halogensubstituent, an alkyl group having 1-8 carbon atoms and having an alkoxysubstituent having 1-8 carbon atoms, an acyl group having 2-8 carbonatoms, an aryl group having 6-10 carbon atoms, or an aralkyl grouphaving an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8carbon atoms.

In some embodiments, each of R²³, R²⁴, R²⁵ and R²⁶ independentlyrepresents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkylgroup having 1-8 carbon atoms and having a halogen substituent.

In some embodiments, Y² is oxygen, sulfur, NR²⁸ or a bond, R²⁸representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkylgroup having 1-8 carbon atoms and having a halogen substituent, an acylgroup having 2-8 carbon atoms, or an alkenyl group having 2-8 carbonatoms.

In some embodiments, Q² represents hydrogen, halogen, hydroxyl, nitro,amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-memberedcycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynylgroup having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms,an alkyl group having 1-8 carbon atoms and having a 3- to 7-memberedcycloalkyl substituent, an alkyl group having 1-8 carbon atoms andhaving a halogen substituent, an alkyl group having 1-8 carbon atoms andan alkoxy substituent having 1-8 carbon atoms, an alkoxy group having1-8 carbon atoms and having a halogen substituent, an acyl group having2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkylgroup having an aryl moiety of 6-10 carbon atoms and an alkylene moietyof 1-8 carbon atoms.

In some embodiments, t is an integer of 1 to 4.

In some embodiments, u is an integer of 1 to 5.

The compounds having the Formula (W) can also be present in the form ofan optical isomer such as enantiomer or racemic body, or a geometricalisomer such as cis or trans. Also provided are isomers of thesecompounds.

The compounds having the Formula (W) can be present in the form of apharmaceutically acceptable salt. Examples of the salt include an alkalimetal salt, such as sodium salt, potassium salt and lithium salt.

In some embodiments, the compound of Formula (W) is a compound shown inTable 11 or pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof.

TABLE 11 Structure Name

3-(3-(2-(3-isopropyl-6-(trifluoromethyl)benzo[b]thiophen-2-yl)ethyl)-5-methylbenzo[d]isoxazol- 6-yl)propan-1-ol

2-((3-(2-(3-isopropyl-6-(trifluoromethyl)benzo[b]thiophen-2-yl)ethyl)-5-methylbenzo[d]isoxazol- 6-yl)oxy)ethan-1-ol

5.2.17. Compounds of Formula (X)

In some embodiments, the compounds of the invention are compounds ofFormula (X):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CD₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

In some embodiments, the compound is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

5.2.18. Compounds of Formula (Y)

In some embodiments, the compounds of the invention are compounds ofFormula (Y):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CO₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

5.2.19. Compounds of Formula (Z)

In some embodiments, the compounds of the invention are compounds ofFormula (Z):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CD₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

5.2.20. Compounds of Formula (AA)

In some embodiments, the compounds of the invention are compounds ofFormula (AA):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   L is (CH₂)₅, which is unsubstituted or substituted by one methyl        group;    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 0 or 1;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   R³ is C₁₋₄ haloalkyl, NO₂, CN, halogen, or C(O)O(C₁₋₄ alkyl);    -   R²⁰ is hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄ alkoxy;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

5.2.21. Additional Compounds

In some embodiments, the compound of the invention is

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

In some embodiments, the compound of the invention is

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

5.3. Compositions of the Invention

In some embodiments, the compositions of the invention comprise (i) aneffective amount of a compound of the invention and (ii) apharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound I or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle. In some embodiments, the compositions ofthe invention comprise (i) an effective amount of a racemate of CompoundI or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the compositions of the invention comprise(i) an effective amount of a mixture of enantiomers of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the compositions of the invention comprise (i) aneffective amount of Compound I or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof, wherein Compound I has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer, and (ii)a pharmaceutically acceptable carrier or vehicle. In some embodiments,the compositions of the invention comprise (i) an effective amount ofCompound I or a pharmaceutically acceptable salt, solvate, ester, amide,or prodrug thereof, wherein Compound I has an hydroxyl-bearing allyliccarbon atom having an (R)-enantiomer, and (ii) a pharmaceuticallyacceptable carrier or vehicle, wherein the compositions aresubstantially free of the (S)-enantiomer of Compound I or apharmaceutically acceptable salt or thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount ofCompound I or a pharmaceutically acceptable salt, solvate, ester, amide,or prodrug thereof, wherein Compound I has an hydroxyl-bearing allyliccarbon atom having an (S)-enantiomer, and (ii) a pharmaceuticallyacceptable carrier or vehicle. In some embodiments, the compositions ofthe invention comprise (i) an effective amount of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound I has an hydroxyl-bearing allylic carbon atomhaving an (S)-enantiomer, and (ii) a pharmaceutically acceptable carrieror vehicle, wherein the compositions are substantially free of the(R)-enantiomer of Compound I or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount of anon-racemic mixture of an (R)-enantiomer and an (S)-enantiomer ofCompound I or a pharmaceutically acceptable salt, solvate, ester, amide,or prodrug thereof and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the non-racemic mixture has an excess of(R)-enantiomer relative to (S)-enantiomer. In some embodiments, thenon-racemic mixture has an excess of (S)-enantiomer relative to(R)-enantiomer.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of a (Z)-isomer of Compound I or a pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug thereof and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecompositions of the invention comprise (i) an effective amount of a(Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptablecarrier or vehicle, wherein the compositions are substantially free ofthe (E)-isomer of Compound I or a pharmaceutically acceptable salt orthereof. In some embodiments, the compositions of the invention comprise(i) an effective amount of an (E)-isomer of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the compositions of the invention comprise (i) aneffective amount of an (E)-isomer of Compound I or a pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug thereof and (ii) apharmaceutically acceptable carrier or vehicle, wherein the compositionsare substantially free of the (Z)-isomer of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof. In some embodiments, the compositions of the invention comprise(i) an effective amount of a non-equal mixture of a (Z)-isomer and an(E)-isomer of Compound I or a pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptablecarrier or vehicle. In some embodiments, the non-equal mixture has anexcess of (Z)-isomer relative to (E)-isomer. In some embodiments, thenon-equal mixture has an excess of (E)-isomer relative to (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound I or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof, wherein Compound I is an(Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the compositions of the invention comprise(i) an effective amount of Compound I or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof, wherein Compound I isan (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds((Z)-(S)-I), ((E)-(R)-I), or ((E)-(S)-I), or a pharmaceuticallyacceptable salt or thereof. In some embodiments, the compositions of theinvention comprise (i) an effective amount of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound I is an (Z)-isomer and has an hydroxyl-bearingallylic carbon atom having an (S)-stereochemistry, and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecompositions of the invention comprise (i) an effective amount ofCompound I or a pharmaceutically acceptable salt, solvate, ester, amide,or prodrug thereof, wherein Compound I is an (Z)-isomer and has anhydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and(ii) a pharmaceutically acceptable carrier or vehicle, wherein thecompositions are substantially free of Compounds ((Z)-(R)-I),((E)-(R)-I), or ((E)-(S)-I), or a pharmaceutically acceptable salt orthereof. In some embodiments, the compositions of the invention comprise(i) an effective amount of Compound I or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof, wherein Compound I isan (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the compositions of the invention comprise(i) an effective amount of Compound I or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof, wherein Compound I isan (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds(E)-(S)-I), ((Z)-(R)-I), or ((Z)-(S)-I), or a pharmaceuticallyacceptable salt or thereof. In some embodiments, the compositions of theinvention comprise (i) an effective amount of Compound I or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound I is an (E)-isomer and has an hydroxyl-bearingallylic carbon atom having an (S)-stereochemistry, and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecompositions of the invention comprise (i) an effective amount ofCompound I or a pharmaceutically acceptable salt, solvate, ester, amide,or prodrug thereof, wherein Compound I is an (E)-isomer and has anhydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and(ii) a pharmaceutically acceptable carrier or vehicle, wherein thecompositions are substantially free of Compounds ((E)-(R)-I),((Z)-(R)-I), or ((Z)-(S)-I), or a pharmaceutically acceptable salt orthereof.

In some embodiments, the composition of the invention comprises (i) aneffective amount of Compound II or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle. In some embodiments, the composition ofthe invention comprises (i) an effective amount of a (Z)-isomer ofCompound II or a pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrieror vehicle. In some embodiments, the composition of the inventioncomprises (i) an effective amount of a (Z)-isomer of Compound II or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle,wherein the compositions are substantially free of the (E)-isomer ofCompound II or a pharmaceutically acceptable salt or thereof. In someembodiments, the composition of the invention comprises (i) an effectiveamount of an (E)-isomer of Compound II or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecomposition of the invention comprises (i) an effective amount of an(E)-isomer of Compound II or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle, wherein the compositions aresubstantially free of the (Z)-isomer of Compound II or apharmaceutically acceptable salt or thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount of anon-equal mixture of a (Z)-isomer and an (E)-isomer of Compound II or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the non-equal mixture has an excess of (Z)-isomerrelative to (E)-isomer. In some embodiments, the non-equal mixture hasan excess of (E)-isomer relative to (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle. In some embodiments, the compositions ofthe invention comprise (i) an effective amount of a racemate of CompoundIII or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the compositions of the invention comprise(i) an effective amount of a mixture of enantiomers of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the compositions of the invention comprise (i) aneffective amount of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof, wherein Compound III has anhydroxyl-bearing allylic carbon atom having an (R)-enantiomer, and (ii)a pharmaceutically acceptable carrier or vehicle. In some embodiments,the compositions of the invention comprise (i) an effective amount ofCompound III or a pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearingallylic carbon atom having an (R)-enantiomer, and (ii) apharmaceutically acceptable carrier or vehicle, wherein the compositionsare substantially free of the (S)-enantiomer of Compound III or apharmaceutically acceptable salt or thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount ofCompound III or a pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearingallylic carbon atom having an (S)-enantiomer, and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecompositions of the invention comprise (i) an effective amount ofCompound III or a pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearingallylic carbon atom having an (S)-enantiomer, and (ii) apharmaceutically acceptable carrier or vehicle, wherein the compositionsare substantially free of the (R)-enantiomer of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof. In some embodiments, the compositions of the invention comprise(i) an effective amount of a non-racemic mixture of an (R)-enantiomerand an (S)-enantiomer of Compound III or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thenon-racemic mixture has an excess of (R)-enantiomer relative to(S)-enantiomer. In some embodiments, the non-racemic mixture has anexcess of (S)-enantiomer relative to (R)-enantiomer.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of a (Z)-isomer of Compound III or a pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug thereof and (ii) apharmaceutically acceptable carrier or vehicle. In some embodiments, thecompositions of the invention comprise (i) an effective amount of a(Z)-isomer of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle, wherein the compositions aresubstantially free of the (E)-isomer of Compound III or apharmaceutically acceptable salt or thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount of an(E)-isomer of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle. In some embodiments, the compositions ofthe invention comprise (i) an effective amount of an (E)-isomer ofCompound III or a pharmaceutically acceptable salt, solvate, ester,amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrieror vehicle, wherein the compositions are substantially free of the(Z)-isomer of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof. In some embodiments, thecompositions of the invention comprise (i) an effective amount of anon-equal mixture of a (Z)-isomer and an (E)-isomer of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof and (ii) a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the non-equal mixture has an excess of (Z)-isomerrelative to (E)-isomer. In some embodiments, the non-equal mixture hasan excess of (E)-isomer relative to (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound III or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof, wherein Compound III is an(Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle. In some embodiments, the compositions of the invention comprise(i) an effective amount of Compound III or a pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug thereof, wherein Compound III isan (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds((Z)-(S)-III), ((E)-(R)-III), or ((E)-(S)-III), or a pharmaceuticallyacceptable salt or thereof. In some embodiments, the compositions of theinvention comprise (i) an effective amount of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound III is an (Z)-isomer and has anhydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and(ii) a pharmaceutically acceptable carrier or vehicle. In someembodiments, the compositions of the invention comprise (i) an effectiveamount of Compound III or a pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof, wherein Compound III is an (Z)-isomerand has an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds((Z)-(R)-III), ((E)-(R)-III), or ((E)-(S)-III), or a pharmaceuticallyacceptable salt or thereof. In some embodiments, the compositions of theinvention comprise (i) an effective amount of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound III is an (E)-isomer and has anhydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and(ii) a pharmaceutically acceptable carrier or vehicle. In someembodiments, the compositions of the invention comprise (i) an effectiveamount of Compound III or a pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomerand has an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry, (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds(E)-(S)-III), ((Z)-(R)-III), or ((Z)-(S)-III), or a pharmaceuticallyacceptable salt or thereof. In some embodiments, the compositions of theinvention comprise (i) an effective amount of Compound III or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein Compound III is an (E)-isomer and has anhydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and(ii) a pharmaceutically acceptable carrier or vehicle. In someembodiments, the compositions of the invention comprise (i) an effectiveamount of Compound III or a pharmaceutically acceptable salt, solvate,ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomerand has an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier orvehicle, wherein the compositions are substantially free of Compounds((E)-(R)-III), ((Z)-(R)-III), or ((Z)-(S)-III), or a pharmaceuticallyacceptable salt or thereof.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound IV or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound V or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound VI or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound VIa or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound VIb or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound VII or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) aneffective amount of Compound VIII or a pharmaceutically acceptable salt,solvate, ester, amide, or prodrug thereof and (ii) a pharmaceuticallyacceptable carrier or vehicle.

In some embodiments, the compositions of the invention further compriseanother therapeutically active agent.

A composition of the invention further comprising anothertherapeutically active agent is a “combination of the invention.” Thepresent invention provides combinations of the invention. Thecombination of the invention can comprise one or more therapeuticallyactive agents.

In some embodiments, the other therapeutically active agent is a lipidlowering drug, a statin, a cholesterol absorption inhibitor, an antibodyagainst PCSK9, an siRNA PCSK9, an anti-fibrotic agent, a thyroidhormone, a selective thyroid receptor-β agonist, apoptosissignal-regulating kinase 1 (ASK1) inhibitor, acetyl-CoA carboxylase(ACC) inhibitor, an integrin antagonist, or a non-steroidal Farnesoid Xreceptor (FXR) agonist.

In some embodiments, the lipid lowering drug is gemfibrozil,fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate,etofylline, pirifibrate, simfibrate, tocofibrate, or pemafibrate. Insome embodiments, the lipid lowering drug is gemfibrozil, fenofibrate,bezafibrate, or pemafibrate.

In some embodiments, statin is atorvastatin, simvastatin, pravastatin,rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin,dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, statin isatorvastatin, simvastatin, pravastatin or rosuvastatin, or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the cholesterol absorption inhibitor is ezetimibe.

In some embodiments, the antibody against PCSK9 is evolocumabalirocumab, bococizumab, 1D05-IgG2 (Merck), RG7652 (Genentech),LY3015014 (Eli Lilly), or LGT-209 (Novartis/Cyon Therapeutics). In someembodiments, the antibody against PCSK9 is evolocumab or alirocumab.

In some embodiments, the siRNA PCSK9 is an siRNA interfering withproduction of PCSK9 such as inclisiran.

In some embodiments, the anti-fibrotic agent is nitazoxamide,tizoxanide, or tizoxanide glucuronide, nintedanib, imatinib, or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the selective thyroid receptor-β agonist is VK2809(Viking Therapeutics), MGL-3196 (Madrigal Pharmaceuticals), MGL-3745(Madrigal Pharmaceuticals), SKL-14763, sobetirome, BCT304 (ITL Pharma),ZYT1 (Zydus Cadila), MB-0781 (Metabasis), or eprotirome.

In some embodiments, the ASK1 inhibitor is selonsertib.

In some embodiments, the ACC inhibitor is firsocostat.

In some embodiments, the integrin antagonist is an α5β1 inhibitor or apan integrin inhibitor. In some embodiments, the integrin antagonist isIDL-2965 (Indalo Therapeutics). In some embodiments, the integrinantagonist is CLT-28643 (ClanoTech AB).

In some embodiments, the integrin antagonist is3-(6-Methoxypyridin-3-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazol-1-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H-indazol-1-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-2-(((Benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-2H-indazol-2-yl)propanoicacid;3-Phenyl-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy)-1H-in-dazol-1-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naph-thyridin-3-yl)methyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)propyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(6-(2-(2-methyl-5,6,7,8-tetrahydro-1,8-na-phthyridin-3-yl)ethyl)-2H-indazol-2-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrazolo[4,3-b]pyridin-1-yl)propanoicacid;3-(5-(2-((4,5-Dihydroimidazol-2-yl)amino)ethoxy)-1H-indazol-1-yl)-3-(6-me-thoxypyridin-3-yl)propanoicacid;3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)-2-((2,4,6-trimethylphenyl)sulfonamido)propanoicacid;2-(((Benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)eth-oxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(Quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(Quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3,5-Dichlorophenyl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-2-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pro-pyl)-1H-indazol-1-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazol-1-yl)propanoicacid;3-(3,5-Dichlorophenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-2-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pro-pyl)-1H-indazol-1-yl)propanoicacid;3-(3-(Dimethylcarbamoyl)phenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)propyl)-1H-indazol-1-yl)propanoicacid;3-(3-(Dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethyl)-1H-indazol-1-yl)propanoicacid;3-(Dibenzo[b,d]furan-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H-indazol-1-yl)propanoicacid;3-(3-((Dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethyl)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)eth-yl)-1H-indazol-1-yl)propanoicacid;3-(3,5-Dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethyl)-1H-indazol-1-yl)propanoicacid;3-(3-(Dimethylcarbamoyl)phenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Dibenzo[b,d]furan-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;6,6,6-Trifluoro-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazol-1-yl)hexanoicacid;3-(3,5-Dichlorophenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-2-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)eth-oxy)-1H-indazol-1-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3-(Dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-2-(((Benzyloxy)carbonyl)amino)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)propyl)-1H-indazol-1-yl)propanoicacid;(R)-3-(3-(Dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(3-(Dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;2-(((Benzyloxy)carbonyl)amino)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-Chloropyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-I)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3,5-Dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3-Fluoro-4-methoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-Cyclopropyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1-H-indazol-1-yl)propanoicacid;3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)octanoicacid;3-(2,3-Dihydrobenzofuran-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Quinolin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethox-y)-1H-indazol-1-yl)propanoicacid (48);3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)-3-(thiophen-2-yl)propanoicacid;3-(Pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)propanoicacid;3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)propanoicacid;3-(3-Cyanophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethox-y)-1H-indazol-1-yl)propanoicacid;3-(5-Fluoropyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-I)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Dibenzo[b,d]furan-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(4,6-Dimethylpyrimidin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-Methylbenzo[d]thiazol-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyr-idin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(4-Phenoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)eth-oxy)-1H-indazol-1-yl)propanoicacid;3-(3-Morpholinophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3-(1H-Pyrrol-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3-((Dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)propanoicacid;3-(3-(2-Oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-Propylpyrazol-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-I)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-2H-indazol-2-yl)propanoicacid;3-(2-Methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(6-Methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)propyl)-2H-indazol-2-yl)propanoicacid;3-(3-(3,5-Dimethylpyrazol-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;4-(4-(Benzyloxy)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)ethoxy)-1H-indazol-1-yl)butanoicacid;3-(6-Methoxypyridin-3-yl)-3-(3-methyl-5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(3S)-3-(6-Methoxypyridin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthyrid-in-2-yl)ethyl)-2H-indazol-2-yl)propanoicacid;4-Phenyl-2-((5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-in-dazol-1-yl)methyl)butanoicacid;3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)propanoicacid;2-(1-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)cyclopropyl)aceticacid;3-(2-Ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;4-(4-Fluorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)etho-xy)-1H-indazol-1-yl)butanoicacid;3-(5-Methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Quinoxalin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)eth-oxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(Quinolin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)e-thyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(6-((2-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-2H-i-ndazol-2-yl)-3-(quinolin-3-yl)propanoicacid;(3S)-3-(Quinolin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)-ethyl)-2H-indazol-2-yl)propanoicacid;(S)-3-(3-(2-Oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(3-(2-Oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-Fluoro-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(Quinolin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)p-ropyl)-2H-indazol-2-yl)propanoicacid;(3S)-3-(Quinolin-3-yl)-3-(6-(3-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-2H-indazol-2-yl)propanoicacid; 3-(5-(Hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy-ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(6-(2-Hydroxy-2-methylpropoxy)-5-methylpyridin-3-yl)-3-(5-(2-(5,6,7,8-t-etrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-3-(5-(2-(5,6,7,8-tetrahy-dro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-Methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-(2-Oxopyrrolidin-1-yl)pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Isoquinolin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)et-hoxy)-1H-indazol-1-yl)propanoicacid;3-(Pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1,8-Naphthyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahy-dro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-2-(((Benzyloxy)carbonyl)amino)-3-(5-((5,6,7,8-tetrahydro-1,8-naphthyr-idin-2-yl)methoxy)-2H-indazol-2-yl)propanoicacid;(R)-3-(5-(Hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-nap-hthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid; (S)-3-(5-(Hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-nap-hthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1,8-Naphthyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(2-Oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)-3-(1-(tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridin-5-yl)propanoicacid;3-(5-(1,3-Dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-((Dimethylamino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(2-Ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(2-Ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetrahyd-ro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(Benzo[d]thiazol-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-I)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-Morpholinopyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-(Methylamino)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy-ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)propanoicacid;3-(6-Methoxypyridazin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-([1,2,4]Triazolo[4,3-a]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(2-Methoxypyrimidin-5-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethyl)-2H-indazol-2-yl)propanoicacid;3-(2-(Azetidin-1-yl)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(Oxazol-5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(7-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid; 3-(5-(((tert-Butoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-Morpholinopyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(Methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(3-Methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(Pyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(Pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy-ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(Pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy-ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-([1,2,4]Triazolo[4,3-a]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(Aminomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-([1,3]Dioxolo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(1,3-Dioxolan-2-yl)-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahyd-ro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(6-(1H-Pyrazol-1-yl)pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-(Pyridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naph-thyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(2-Methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(1H-pyrazol-5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(6-morpholinopyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyri-din-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(6-methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(morpholine-4-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(dimethylcarbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-nap-hthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrah-ydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-cyclopropylpyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridi-n-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(azetidine-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid;3-(5-((2-(dimethylamino)ethyl)carbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-te-trahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)hexanoicacid;3-(5-(dimethylamino)pyridin-3-yl)-3-(5-(2(5,6,7,8-tetrahydro-1,8-naphthyr-idin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-cyclohexyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-na-phthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid; (S)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetra-hydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-t-etrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-t-etrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(methylsulfonamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1-,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(acetamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-napht-hyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;3-(5-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl-)-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)propanoicacid;4-((6-(2-Carboxy-1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)ethyl)pyrazin-2-yl)amino)butanoicacid;3-(6-Methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H-indazol-1-yl)propanoicacid;(R)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoicacid;(S)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoicacid;(R)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoicacid;(S)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy-)-1H-indazol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoicacid;3-(6-Methoxypyridin-3-yl)-3-(5-(2-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)ethoxy)-1H-indazol-1-yl)propanoicacid;(S)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethoxy)-1H-inda-zol-1-yl)-3-(6-methoxypyridin-3-yl)propanoicacid; and(R)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethoxy)-1H-inda-zol-1-yl)-3-(6-methoxypyridin-3-yl)propanoicacid; or a pharmaceutically acceptable salt thereof. See US2019/0256496, which is hereby incorporated by reference it its entirety.

In some embodiments, the integrin antagonist is(S)-3-(3-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-nap-hthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-3-(3-((R)-2-methoxypropoxylphenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-3-(3-((S)-2-methoxypropoxylphenyl)-4-4R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-3-(3-(2-methoxy-2-methylpropoxy)phenyl)-44(R)-3-(2-(5,6,7,8-tetrahydr-o-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;3-(3-(((S)-1-methoxypropan-2-yl)oxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahyd-ro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidi-n-1-yl)-3-(3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)butanoicacid;(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidi-n-1-yl)-3-(3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)butanoicacid;(S)-3-(3,5-Bis(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(3S)-4-((R)-3-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolid-in-1-yl)-3-(3-(tetrahydrofuran-3-yl)phenyebutanoicacid;(3S)-4-((R)-3-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolid-in-1-yl)-3-(3-(tetrahydrofuran-3-yl)phenyebutanoicacid;(S)-3-(3-((1-methoxy-2-methylpropan-2-yl)oxy)phenyl)-4-4R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-3-(3-(((R)-1-methoxypropan-2-yl)oxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetr-ahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-3-(3-(2-Isopropoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;(S)-4-((R)-3-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidi-n-1-yl)-3-(3-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoicacid;(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidi-n-1-yl)-3-(3-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoicacid;(S)-3-(2-Fluoro-5-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydr-o-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;3-(3-((1,3-Dimethoxypropan-2-yeoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydr-o-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;3-(3-(2-Fluoroethoxy)-5-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tet-rahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid;3-(3-(3-Methoxypropoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid; or3-(3-(Oxetan-3-ylmethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naph-thyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid; or a pharmaceutically acceptable salt thereof. See US2019/0112306, which is hereby incorporated by reference it its entirety.

In some embodiments, the integrin antagonist has the structure

pharmaceutically acceptable salt thereof. See U.S. Pat. No. 10,214,522,which is hereby incorporated by reference it its entirety.

In some embodiments, the integrin antagonist has the structure

or a pharmaceutically acceptable salt thereof. See US 2018/0072684,which is hereby incorporated by reference it its entirety.

In some embodiments, the non-steroidal Farnesoid X receptor (FXR)agonist is cilofexor.

In some embodiments, the combinations of the invention compriseselonsertib, firsocostat or cilofexor. In some embodiments, thecombinations of the invention comprise selonsertib and firsocostat. Insome embodiments, the combinations of the invention comprisesselonsertib and cilofexor. In some embodiments, the combinations of theinvention comprises fircosostat and cilofexor. In some embodiments, thecombinations of the invention comprise selonsertib, firsocostat andcilofexor.

In some embodiments, the pharmaceutically acceptable carrier or vehicleincludes, but is not limited to, a binder, filler, diluent,disintegrant, wetting agent, lubricant, glidant, coloring agent,dye-migration inhibitor, sweetening agent or flavoring agent.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof.

Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. In some embodiments, the binder ishydroxypropylcellulose.

The binder or filler can be present from about 2% to about 49% by weightof the compositions of the invention provided herein or any range withinthese values. In some embodiments, the binder or filler is present inthe composition of the invention from about 5% to about 15% by weight.In some embodiments, the binder or filler is present in the compositionof the invention at about 5%, about 6%, about 7%, about 8%, about 9%,about 8%, about 10%, about 11%, about 12%, about 13%, about 14%, orabout 15% by weight or any range within any of these values.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Insome embodiments, the diluent is lactose monohydrate. In someembodiments, the diluent is lactose monohydrate Fast-Flo 316 NF.

The compositions of the invention can comprise a diluent, e.g., fromabout 5% to about 49% of a diluent by weight of composition or any rangebetween any of these values. In some embodiments, the diluent is presentin the compositions of the invention from about 15% to about 30% byweight. In some embodiments, the diluent is present in the compositionof the invention at about 15%, about 16%, about 17%, about 18%, about19%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%,about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% byweight or any range within any of these values.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thecompositions of the invention can vary. In some embodiments, thedisintegrant is croscarmellose sodium. In some embodiments, thedisintegrant is croscarmellose sodium NF (Ac-Di-Sol).

The compositions of the invention can comprise a disintegrant, e.g.,from about 0.5% to about 15% or from about 1% to about 10% by weight ofa disintegrant. In some embodiments, the compositions of the inventioncomprise a disintegrant in an amount of about 5%, about 6%, about 7%,about 8%, about 9%, about 8%, about 10%, about 11%, about 12%, about13%, about 14%, or about 15% by weight of the composition or in anyrange within any of these values.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. In some embodiments, thelubricant is magnesium stearate.

The compositions of the invention can comprise a lubricant, e.g., about0.1 to about 5% by weight of a lubricant. In some embodiments, thecompositions of the invention comprise a lubricant in an amount of about0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%,2.8%, 2.9%, or 3.0%, by weight of the composition or in any range withinany of these values.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and talc, including asbestos-free talc.

Coloring agents include any of the approved, certified, water solubleFD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate,and color lakes and mixtures thereof.

Flavoring agents include natural flavors extracted from plants, such asfruits, and synthetic blends of compounds that provide a pleasant tastesensation, such as peppermint and methyl salicylate.

Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin,sucralose, and artificial sweeteners, such as saccharin, stevioside(Stevia) and aspartame.

Suitable emulsifying agents include gelatin, acacia, tragacanth,bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate(TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), andtriethanolamine oleate. Suspending and dispersing agents include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

Examples of non-aqueous liquids utilized in emulsions include mineraloil and cottonseed oil. Organic acids include citric and tartaric acid.Sources of carbon dioxide include sodium bicarbonate and sodiumcarbonate.

The compounds of the invention and the compositions of the invention canbe formulated for administration by a variety of means including orally,parenterally, by inhalation spray, topically, or rectally informulations containing pharmaceutically acceptable carriers, adjuvantsand vehicles. The term “parenteral” as used here includes subcutaneous,intravenous, intramuscular, and intraarterial injections with a varietyof infusion techniques. Intraarterial and intravenous injection as usedherein includes administration through catheters.

The compounds of the invention and the compositions of the invention canbe formulated in accordance with the routine procedures adapted fordesired administration route. Accordingly, the compositions of theinvention can take such forms as suspensions, solutions or emulsions inoily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents. The compounds of theinvention and the compositions of the invention can be formulated as apreparation suitable for implantation or injection. Thus, for example,the compositions of the invention can be formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives (e.g., as a sparingly soluble salt). The compounds of theinvention and the compositions of the invention can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use. Suitable formulations for each of these methods ofadministration can be found, for example, in Remington: The Science andPractice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott,Williams & Wilkins, Philadelphia, Pa.

In some embodiments, the compositions of the invention are suitable fororal administration. These compositions can comprise solid, semisolid,gelmatrix or liquid dosage forms suitable for oral administration. Asused herein, oral administration includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, withoutlimitation, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups orany combination thereof. In some embodiments, compositions of theinvention suitable for oral administration are in the form of a tabletor a capsule. In some embodiments, the composition of the invention isin a form of a tablet. In some embodiments, the composition of theinvention is in a form of a capsule. In some embodiments, the compoundof the invention is contained in a capsule.

In some embodiments, capsules are immediate release capsules.Non-limiting example of a capsule is a Coni-snap® hard gelatin capsule.

The compositions of the invention can be in the form of compressedtablets, tablet triturates, chewable lozenges, rapidly dissolvingtablets, multiple compressed tablets, or enteric-coating tablets,sugar-coated, or film-coated tablets. Enteric-coated tablets arecompressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which can be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. A film coating can impart the same general characteristics asa sugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

In some embodiments, the coating is a film coating. In some embodiments,the film coating comprises Opadry White and simethicone emulsion 30%USP.

In some embodiments, the compound of the invention is contained in atablet. In some embodiments, the compound of the invention is containedin a compressed tablet. In some embodiments, the compound of theinvention is contained in a film-coated compressed tablet. In someembodiments, the compositions of the invention are in the form offilm-coated compressed tablets.

In some embodiments, the compositions of the invention is prepared byfluid bed granulation of the compound of the invention with one or morepharmaceutically acceptable carrier, vehicle, or excipients. In someembodiments, the compositions of the invention prepared by fluid bedgranulation process can provide tablet formulation with goodflowability, good compressibility, fast dissolution, good stability,and/or minimal to no cracking. In some embodiments, the fluid bedgranulation process allows preparation of formulations having high drugloading, such as over 70% or over 75% of a compound of the invention.

The compositions of the invention can be in the form of soft or hardcapsules, which can be made from gelatin, methylcellulose, starch, orcalcium alginate. The hard gelatin capsule, also known as the dry-filledcapsule (DFC), can comprise of two sections, one slipping over theother, thus completely enclosing the active ingredient. The soft elasticcapsule (SEC) is a soft, globular shell, such as a gelatin shell, whichis plasticized by the addition of glycerin, sorbitol, or a similarpolyol. The soft gelatin shells can contain a preservative to preventthe growth of microorganisms. Suitable preservatives are those asdescribed herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein canbe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules can also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The compositions of the invention can be in liquid or semisolid dosageforms, including emulsions, solutions, suspensions, elixirs, and syrups.An emulsion can be a two-phase system, in which one liquid is dispersedin the form of small globules throughout another liquid, which can beoil-in-water or water-in-oil. Emulsions can include a pharmaceuticallyacceptable non-aqueous liquids or solvent, emulsifying agent, andpreservative. Suspensions can include a pharmaceutically acceptablesuspending agent and preservative. Aqueous alcoholic solutions caninclude a pharmaceutically acceptable acetal, such as a di-(loweralkyl)acetal of a lower alkyl aldehyde (the term “lower” means an alkylhaving between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal;and a water-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs can be clear, sweetened, andhydroalcoholic solutions. Syrups can be concentrated aqueous solutionsof a sugar, for example, sucrose, and can comprise a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol canbe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

The compositions of the invention for oral administration can be alsoprovided in the forms of liposomes, micelles, microspheres, ornanosystems. Miccellar dosage forms can be prepared as described in U.S.Pat. No. 6,350,458.

The compositions of the invention can be provided as non-effervescent oreffervescent, granules and powders, to be reconstituted into a liquiddosage form. Pharmaceutically acceptable carriers and excipients used inthe non-effervescent granules or powders can include diluents,sweeteners, and wetting agents. Pharmaceutically acceptable carriers andexcipients used in the effervescent granules or powders can includeorganic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms. And, flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The compositions of the invention can be formulated as immediate ormodified release dosage forms, including delayed-, extended, pulsed-,controlled, targeted-, and programmed-release forms.

In some embodiments, the compositions of the invention comprise afilm-coating.

The compositions of the invention can comprise another active ingredientthat does not impair the composition's therapeutic or prophylacticefficacy or can comprise a substance that augments or supplements thecomposition's efficacy.

The tablet dosage forms can comprise the compound of the invention inpowdered, crystalline, or granular form, and can further comprise acarrier or vehicle described herein, including binder, disintegrant,controlled-release polymer, lubricant, diluent, or colorant.

In some embodiments, the compositions of the invention can furthercomprise an excipient such as a diluent, a disintegrant, a wettingagent, a binder, a glidant, a lubricant, or any combination thereof. Insome embodiments, a tablet comprises a binder. And, in some embodiments,the binder comprises microcrystalline cellulose, dibasic calciumphosphate, sucrose, corn starch, polyvinylpyrridone, hydroxypropylcellulose, hydroxymethyl cellulose, or any combination thereof. In otherembodiments, the tablet comprises a disintegrant. In other embodiments,the disintegrant comprises sodium croscarmellose, sodium starchglycolate, or any combination thereof. In other embodiments, the tabletcomprises a lubricant. And, in some embodiments, the lubricant comprisesmagnesium stearate stearic acid, hydrogenated oil, sodium stearylfumarate, or any combination thereof.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a binder such as any of the binders describedherein.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a disintegrant such as any of thedisintegrants described herein.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a lubricant such as any of the lubricantsdescribed herein.

In some embodiments, the compositions of the invention can be in amodified release or a controlled release dosage form. In someembodiments, the compositions of the invention can comprise particlesexhibiting a particular release profile. For example, the composition ofthe invention can comprise a compound of the invention in an immediaterelease form while also comprising a statin or a pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug thereof in a modifiedrelease form, both compressed into a single tablet. Other combinationand modification of release profile can be achieved as understood by oneskilled in the art. Examples of modified release dosage forms suited forpharmaceutical compositions of the instant invention are described,without limitation, in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108;5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

In some embodiments, the compositions of the invention are amatrix-controlled release dosage form. In some embodiments, the releaseprofile of the compound of the invention and of the otherpharmaceutically active agent is the same or different. Suitablematrix-controlled release dosage forms are described, for example, inTakada et al in “Encyclopedia of Controlled Drug Delivery,” Vol. 2,Mathiowitz ed., Wiley, 1999.

In some embodiments, the matrix-controlled release form comprises anerodible matrix comprising water-swellable, erodible, or solublepolymers, including synthetic polymers, and naturally occurring polymersand derivatives, such as polysaccharides and proteins.

In some embodiments, the erodible matrix of the matrix-controlledrelease form comprises chitin, chitosan, dextran, or pullulan; gum agar,gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans,gum ghatti, guar gum, xanthan gum, or scleroglucan; starches, such asdextrin or maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC),carrrboxymethyl ethyl cellulose (CMEC,) hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CP), cellulose butyrate (CB), cellulose acetate butyrate(CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate(CAT), hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), orethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinylalcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide;polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; or other acrylic acidderivatives, such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, or (trimethylaminoethyl)methacrylatechloride; or any combination thereof.

In other embodiments, the compositions of the invention are in amatrix-controlled modified release form comprising a non-erodiblematrix. In some embodiments, the statin, the compound of the inventionis dissolved or dispersed in an inert matrix and is released primarilyby diffusion through the inert matrix once administered. In someembodiments, the non-erodible matrix of the matrix-controlled releaseform comprises an insoluble polymer, such as polyethylene,polypropylene, polyisoprene, polyisobutylene, polybutadiene,polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene,polyvinylchloride, a methyl acrylate-methyl methacrylate copolymer, anethylene-vinylacetate copolymer, an ethylene/propylene copolymer, anethylene/ethyl acrylate copolymer, a vinylchloride copolymer with vinylacetate, a vinylidene chloride, an ethylene or a propylene, an ionomerpolyethylene terephthalate, a butyl rubber epichlorohydrin rubber, anethylene/vinyl alcohol copolymer, an ethylene/vinyl acetate/vinylalcohol terpolymer, an ethylene/vinyloxyethanol copolymer, a polyvinylchloride, a plasticized nylon, a plasticized polyethyleneterephthalate,a natural rubber, a silicone rubber, a polydimethylsiloxane, a siliconecarbonate copolymer, or a hydrophilic polymer, such as an ethylcellulose, a cellulose acetate, a crospovidone, or a cross-linkedpartially hydrolyzed polyvinyl acetate; a fatty compound, such as acarnauba wax, a microcrystalline wax, or a triglyceride; or anycombination thereof.

The compositions of the invention that are in a modified release dosageform can be prepared by methods known to those skilled in the art,including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

In some embodiments, the compositions of the invention comprise atablets-in-capsule system, which can be a multifunctional and multipleunit system comprising versatile mini-tablets in a hard gelatin capsule.The mini-tablets can be rapid-release, extended-release, pulsatile,delayed-onset extended-release minitablets, or any combination thereof.In some embodiments, combinations of mini-tablets or combinations ofmini-tablets and minibeads comprising multiple active pharmaceuticalagents can each have specific lag times, of release multiplied pulsatiledrug delivery system (DDS), site-specific DDS, slow-quick DDS,quick/slow DDS and zero-order DDS.

In some embodiments, the compositions of the invention are in anosmotic-controlled release dosage form.

In some embodiments, the osmotic-controlled release device comprises aone-chamber system, a two-chamber system, asymmetric membrane technology(AMT), an extruding core system (ECS), or any combination thereof. Insome embodiments, such devices comprise at least two components: (a) thecore which contains the active pharmaceutical agent(s); and (b) asemipermeable membrane with at least one delivery port, whichencapsulates the core. The semipermeable membrane controls the influx ofwater to the core from an aqueous environment of use so as to cause drugrelease by extrusion through the delivery port(s).

In some embodiments, the core of the osmotic device optionally comprisesan osmotic agent, which creates a driving force for transport of waterfrom the environment of use into the core of the device. One class ofosmotic agents useful in the compositions of invention compriseswater-swellable hydrophilic polymers, which are also referred to as“osmopolymers” or “hydrogels,” including, but not limited to,hydrophilic vinyl and acrylic polymers, polysaccharides such as calciumalginate, polyethylene oxide (PEO), polyethylene glycol (PEG),polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate),poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP),cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVPcopolymers with hydrophobic monomers such as methyl methacrylate andvinyl acetate, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolate.

Another class of osmotic agents useful in the compositions of theinvention comprises osmogens, which are capable of imbibing water toaffect an osmotic pressure gradient across the barrier of thesurrounding coating. Suitable osmogens include, but are not limited to,inorganic salts, such as magnesium sulfate, magnesium chloride, calciumchloride, sodium chloride, lithium chloride, potassium sulfate,potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate,potassium chloride, and sodium sulfate; sugars, such as dextrose,fructose, glucose, inositol, lactose, maltose, mannitol, raffinose,sorbitol, sucrose, trehalose, and xylitol; organic acids, such asascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid,sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid,p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; andmixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the compound of the invention dissolves followingadministration. For example, an amorphous sugar, such as Mannogeme EZ(SPI Pharma, Lewes, Del.) can be included to provide faster deliveryduring the first couple of hours (e.g., about 1 to about 5 hrs) topromptly produce prophylactic or therapeutic efficacy, and gradually andcontinually release of the remaining amount to maintain the desiredlevel of therapeutic or prophylactic effect over an extended period oftime. In some embodiments, the compound of the invention is releasedfrom the compositions of the invention at such a rate to replace theamount of the compound of the invention metabolized or excreted by thesubject.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful for forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

The semipermeable membranes can also be a hydrophobic microporousmembrane, wherein the pores are substantially filled with a gas and arenot wetted by the aqueous medium but are permeable to water vapor, asdisclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vaporpermeable membrane are typically composed of hydrophobic polymers suchas polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the compound of the invention released and therelease rate can substantially be modulated via the thickness andporosity of the semipermeable membrane, the composition of the core, andthe number, size, and position of the delivery ports.

In some embodiments, the pharmaceutical composition in an osmoticcontrolled-release dosage form can further comprise additionalconventional excipients as described herein to promote performance orprocessing of the formulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In some embodiments, the pharmaceutical composition provided herein isformulated as asymmetric membrane technology (AMT) controlled-releasedosage form that comprises an asymmetric osmotic membrane that coats acore comprising the active ingredient(s) and other pharmaceuticallyacceptable excipients. See, U.S. Pat. No. 5,612,059 and WO 2002/17918.The AMT controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In some embodiments, the pharmaceutical composition provided herein isformulated as ESC controlled-release dosage form that comprises anosmotic membrane that coats a core comprising the compound of theinvention, hydroxylethyl cellulose, and other pharmaceuticallyacceptable excipients.

In some embodiments, the compositions of the invention are a modifiedrelease dosage form that is fabricated as a multiparticulate-controlledrelease dosage form that comprises a plurality of particles, granules,or pellets, microparticulates, beads, microcapsules and microtablets,ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, orfrom about 100 μm to 1 mm in diameter.

The multiparticulate-controlled release dosage forms can provide aprolonged release dosage form with an improved bioavailability. Suitablecarriers to sustain the release rate of the compound of the inventioninclude, without limitation, ethyl cellulose, HPMC, HPMC-phtalate,colloidal silicondioxide and Eudragit-RSPM.

Compositions of the invention in pellet form can comprise 50-80% (w/w)of a drug and 20-50% (w/w) of microcrystalline cellulose or otherpolymers. Suitable polymers include, but are not limited to,microcrystalline wax, pregelatinized starch and maltose dextrin.

Beads can be prepared in capsule and tablet dosage forms. Beads intablet dosage form can demonstrate a slower dissolution profile thanmicroparticles in capsule form. Microparticle fillers suitable forcompositions and therapeutic or prophylactic methods of the inventioninclude, without limitation, sorbitan monooleate (Span 80), HPMC, or anycombination thereof. Suitable dispersions for controlled release latexinclude, for example, ethyl-acrylate and methyl-acrylate.

In some embodiments, the compositions of the invention are in the formor microcapsules and/or microtablets. In some embodiments, microcapsulescomprise extended release polymer microcapsules containing a statin anda compound of the invention with various solubility characteristics.Extended release polymer microcapsules can be prepared with colloidalpolymer dispersion in an aqueous environment. In other embodiments,microcapsules suitable for the compositions and methods provided hereincan be prepared using conventional microencapsulating techniques(Bodmeier & Wang, 1993).

Such multiparticulates can be made by the processes known to thoseskilled in the art, including wet- and dry-granulation,extrusion/spheronization, roller-compaction, melt-congealing, and byspray-coating seed cores. See, for example, Multiparticulate Oral DrugDelivery; Marcel Dekker: 1994; and Pharmaceutical PelletizationTechnology; Marcel Dekker: 1989. Excipients for such technologies arecommercially available and described in US Pharmacopeia.

Other excipients as described herein can be blended with thecompositions of the invention to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate dosage form or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, or water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

In other embodiments, the compositions of the invention are in a dosageform that has an instant releasing component and at least one delayedreleasing component, and is capable of giving a discontinuous release ofthe compound in the form of at least two consecutive pulses separated intime from 0.1 hr to 24 hrs.

In some embodiments, the compositions of the invention comprise fromabout 1 mg to about 1000 mg of a compound of the invention or any amountranging from and to these values. In some embodiments, the compositionsof the invention comprise from about 1 mg to about 500 mg of a compoundof the invention or any amount ranging from and to these values. In someembodiments, the compositions of the invention comprise from about 1 mgto about 400 mg of a compound of the invention or any amount rangingfrom and to these values.

In other embodiments, the compositions of the invention comprise acompound of the invention in an amount that is a molar equivalent toabout 1 mg to about 1000 mg of a compound of the invention or any amountranging from and to these values. In other embodiments, the compositionsof the invention comprise a compound of the invention in an amount thatis a molar equivalent to about 1 mg to about 500 mg of a compound of theinvention or any amount ranging from and to these values. In otherembodiments, the compositions of the invention comprise a compound ofthe invention in an amount that is a molar equivalent to about 1 mg toabout 400 mg of a compound of the invention or any amount ranging fromand to these values.

In some embodiments, the compositions of the invention comprise acompound of the invention in an amount of about 10 wt % to about 99 wt %of the total weight of the composition of the invention.

5.4. Methods of the Invention

The present invention provides methods for treating or preventing aliver disorder, dyslipidemia, dyslipoproteinemia, a renal disease, adisorder of glucose metabolism, a disorder of lipid metabolism, adisorder of glucid metabolism, a cardiovascular disease, a vasculardisease, a metabolic syndrome, a complication associated with metabolicsyndrome, a PPAR-associated disorder, septicemia, a thrombotic disorder,obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis,pancreatitis, a cerebrovascular disease, a disorder related toneovascularization, hypertension, cancer, inflammation, an inflammatorydisease, a neurodegenerative disease, an autoimmune disease, aneoplastic disease, muscle atrophy, cholestasis, mitochondrialdysfunction, an ocular disease, a lysosomal storage disease, orimpotence, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. The present invention provides methods for treating orpreventing a kidney disease (e.g., acute kidney injury), comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention.

In some embodiments, the present invention provides methods for treatingor preventing a liver disorder, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the liver disorderinvolves pathological disruption, inflammation, degeneration, apoptosis,or proliferation of liver cells. In some embodiments, the liver disorderis liver fibrosis, fatty liver disease, non-alcoholic fatty liverdisease (NAFLD) or non-alcoholic steatohepatitis (NASH).

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of alanine transaminase (ALT),aspartate transaminase (AST), alkaline phosphatase (ALP), bilirubin,gamma-glutamyltransferase (GGT), L-lactate dehydrogenase (LD),prothrombin time (PT), creatinine, or total protein in a subject's bloodplasma or blood serum, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the present inventionprovides methods for elevating an abnormally low concentration ofalbumin or total protein, in a subject's blood plasma or blood serum,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

An “abnormally high concentration” of ALT in a subject's blood plasma orblood serum is greater than 56 units/liter. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of ALT in a subject's blood plasma or blood serum rangesfrom about 7 units/liter to about 56 units/liter.

An “abnormally high concentration” of AST in a subject's blood plasma orblood serum is greater than 48 units/liter. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of AST in a subject's blood plasma or blood serum rangesfrom about 8 units/liter to about 48 units/liter.

An “abnormally high concentration” of ALP in a subject's blood plasma orblood serum is greater than 129 units/liter. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of ALP in a subject's blood plasma or blood serum rangesfrom about 40 units/liter to about 129 units/liter.

An “abnormally low concentration” of albumin in a subject's blood plasmaor blood serum is less than 3.5 g/dL. In some embodiments, the elevatingis to a normal concentration. In some embodiments, the normalconcentration of albumin in a subject's blood plasma or blood serumranges from about 3.5 g/dL to about 5.0 g/dL.

An “abnormally high concentration” of bilirubin in a subject's bloodplasma or blood serum is greater than 1.2 mg/dL. In some embodiments,the reducing is to a normal concentration. In some embodiments, thenormal concentration of bilirubin in a subject's blood plasma or bloodserum ranges from about 0.1 mg/dL to about 1.2 mg/dL.

An “abnormally high concentration” of GGT in a subject's blood plasma orblood serum is greater than 61 units/liter. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of GGT in a subject's blood plasma or blood serum rangesfrom about 8 units/liter to about 61 units/liters.

An “abnormally high concentration” of LD in a subject's blood plasma orblood serum is greater than 222 units/liter. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of LD in a subject's blood plasma or blood serum rangesfrom about 122 units/liter to about 222 units/liters.

An “abnormally high concentration” of PT in a subject's blood plasma orblood serum is greater than 12.5 seconds. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of PT in a subject's blood plasma or blood serum rangesfrom about 9.4 seconds to about 12.5 seconds.

An “abnormally high concentration” of creatinine in a subject's bloodplasma or blood serum is greater than 1.5 mg/dL, which corresponds to aglomerular filtration rate (GFR) of approximately 30 mL/min andindicative of renal failure. In some embodiments, the reducing is to anormal concentration. In some embodiments, the normal concentration ofcreatinine in a subject's blood plasma or blood serum ranges from about0.84 mg/dL to about 1.21 mg/dL. (about 74.3 μmol/L to about 107 μmol/L).

An “abnormally high concentration” of total protein in a subject's bloodplasma or blood serum is greater than 7.9 g/dL. An “abnormally lowconcentration” of total protein in a subject's blood plasma or bloodserum is less than 6.3 g/dL. In some embodiments, the reducing is to anormal concentration. In some embodiments, the elevating is to a normalconcentration. In some embodiments, the normal concentration of totalprotein in a subject's blood plasma or blood serum ranges from about 6.3g/dL to about 7.9 g/dL.

In some embodiments, the present invention provides methods for treatingor preventing NAFLD or NASH, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or thecomposition of the invention.

In some embodiments, the present invention provides methods for treatingor preventing dyslipidemia, comprising administering to a subject inneed thereof an effective amount of the compound of the invention or thecomposition of the invention. In some embodiments, the dyslipidemia ishyperlipidemia or an abnormally low concentration of high densitylipoprotein cholesterol (HDL-C) in the subject's blood plasma or bloodserum. The term “dyslipidemia” refers to a disorder that leads to or ismanifested by an aberrant level of circulating lipids.

In some embodiments, the present invention provides methods forrestoring blood plasma or blood serum concentration oftotal-cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C,non-HDL-C or free triglycerides to a normal or recommended concentrationor ratio. Accordingly, to the extent that levels of lipids in the bloodplasma or blood serum are abnormally high, the compounds of theinvention or the compositions of the invention can be administered to apatient to restore normal levels. Normal levels of lipids are well knownto those skilled in the art. For example, normal blood levels oftotal-cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C,non-HDL-C, free triglycerides and others parameters relating to lipidmetabolism can be found at the web site of the American HeartAssociation, The National Lipid Association and that of the NationalCholesterol Education Program of the National Heart, Lung and BloodInstitute. In some embodiments, a recommended concentration of HDL-C inthe blood plasma or the blood serum is above 35 mg/dl. In someembodiments, a recommended concentration of LDL-C in the blood plasma orthe blood serum is below 100 mg/dl. In some embodiments, a recommendedLDL-C:HDL-C ratio in the blood plasma or in the blood serum is below5:1, in some embodiments, 3.5:1. In some embodiments, a recommendedconcentration of free triglycerides in the blood plasma or the bloodserum is less than 200 mg/dl.

In some embodiments, the present invention provides methods for treatingor preventing hyperlipidemia, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, hyperlipidemia ishypercholesterolemia, familial hypercholesterolemia,hypertriglyceridemia, or familial combined hyperlipidemia. In someembodiments, hyperlipidemia is characterized by an abnormally reduced ordeficient lipoprotein lipase level or activity in the subject's bloodplasma or blood serum, or an abnormally high concentration of ketonebodies, lipoprotein(a) cholesterol (Lp(a)-C), low density lipoprotein(LDL), very low density lipoproteins cholesterol (VLDL-C) ornon-esterified fatty acids (NEFA) in the subject's blood plasma or bloodserum. In some embodiments, the reduced or deficient lipoprotein lipaselevel or activity is a result of a lipoprotein lipase mutation. In someembodiments, the reduced or deficient lipoprotein lipase level oractivity is a result of a mutation in a gene encoding a lipoproteinlipase.

Non-limiting examples of ketone bodies include acetoacetate,beta-hydroxybutyrate, and acetone. An “abnormally high concentration” ofketone bodies in a subject's blood plasma or blood serum is 1 mg/dL orgreater (<0.1 mmol/L). In some embodiments, the present inventionprovides methods for reducing an abnormally high concentration of ketonebodies in a subject's blood plasma or blood serum, wherein theconcentration is 1 mg/dL or greater. In some embodiments, the reducingis to a normal level. In some embodiments, the normal level is less than1 mg/dL (<0.1 mmol/L). See Devkota, B. P. et al. Medscape emedicine,updated Oct. 30, 2015.

An “abnormally high concentration” of VLDL-C in a subject's blood plasmaor blood serum is greater than 30 mg/dL (1.7 mmol/L). In someembodiments, the present invention provides methods for reducing VLDL-Cconcentration in a subject's blood plasma or blood serum, wherein theVLDL-C concentration is greater than 30 mg/dL. In some embodiments, thereducing is to a normal level. In some embodiments, the normal levelranges from 2 mg/dL to 30 mg/dL (0.1 to 1.7 mmol/L).

An “abnormally high concentration” of NEFA is in a subject's bloodplasma or blood serum in a non-fasting state is 0.9 mM or greater. An“abnormally high concentration” of NEFA in a subject's blood plasma orblood serum in a fasting state is greater than 1.8 mM at a fastingstate. An “abnormally high concentration” of NEFA in a subject's bloodplasma or blood serum at 15-hour fasting is greater than 1.1 nM. An“abnormally high concentration” of NEFA in a subject's blood plasma orblood serum at 20-hour fasting is greater than 1.3 mM. An “abnormallyhigh concentration” of NEFA in a subject's blood plasma or blood serumat 15-hour fasting is greater than 1.1 nM. An “abnormally highconcentration” of NEFA in a subject's blood plasma or blood serum at24-hour fasting is greater than 1.8 mM. In some embodiments, the presentinvention provides methods for reducing NEFA concentration in asubject's blood plasma or blood serum, wherein the NEFA concentration isgreater than 0.9 mM, in some embodiments greater than 1.1 mM, in someembodiments greater than 1.5 mM and in some embodiments greater than 1.8mM. In some embodiments, the reducing is to a normal level. In someembodiments, the normal level is 1.8 mM or less, in some embodiments 1.5mM or less, in some embodiments 1.1 mM or less and in some embodiments0.9 mM or less. See Horowitz, G. L. et al. Medscape emedicine, updatedJul. 25, 2019.

In some embodiments, the present invention provides methods for treatingor preventing dyslipoproteinemia, comprising administering to a subjectin need thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, thedyslipoproteinemia is characterized by an abnormally high concentrationof LDL, apolipoprotein (a) or VLDL in a subject's blood plasma or bloodserum, or an abnormally low concentration of high density lipoprotein(HDL) or lipoprotein lipase in a subject's blood plasma or blood serum.In some embodiments, the abnormally low concentration of the lipoproteinlipase is associated with: a lipoprotein lipase mutation,hypoalphalipoproteinemia, a lipoprotein abnormality associated withdiabetes, a lipoprotein abnormality associated with obesity, alipoprotein abnormality associated with Alzheimer's disease, or familialcombined hyperlipidemia. The term “dyslipoproteinemia” refers to adisorder that leads to or is manifested by an aberrant concentration ofcirculating lipoproteins in a subject's blood plasma or blood serum. Tothe extent that the concentrations of lipoproteins in the blood plasmaor blood serum are too high, the compounds of the invention or thecompositions of the invention can be administered to the subject torestore to normal concentrations of lipoproteins. Conversely, to theextent that the concentrations of lipoproteins in the blood plasma orblood serum are too low, the compounds of the invention or thecompositions of the invention can be administered to the subject torestore to normal concentrations. Normal concentrations of lipoproteinsare reported in medical treatises known to those of skill in the art.

In some embodiments, the present invention provides methods for treatingor preventing a renal disease, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the renal disease isa glomerular disease, a tubular disease, a tubulointerstitial disease,acute or rapidly progressive renal failure, chronic renal failure,nephrolithiasis, or a tumor. In some embodiments, the renal disease ishypertension, nephrosclerosis, microangiopathic hemolytic anemia,atheroembolic renal disease, diffuse cortical necrosis, or a renalinfarct.

In some embodiments, the glomerular disease is an acuteglomerulonephritis, a chronic glomerulonephritis, a rapidly progressiveglomerulonephritis, a nephrotic syndrome, a focal proliferativeglomerulonephritis, a glomerular lesion associated with systemicdisease, Goodpasture syndrome, multiple myeloma, diabetes, neoplasia,sickle cell disease or a chronic inflammatory disease. In someembodiments, the glomerular lesion associated with systemic disease issystemic lupus erythematosus.

In some embodiments, the tubular disease is an acute tubular necrosis,an acute renal failure, a polycystic renal disease, medullary spongekidney, a medullary cystic disease, nephrogenic diabetes, or a renaltubular acidosis.

In some embodiments, the tubulointerstitial disease is pyelonephritis, adrug- or toxin-induced tubulointerstitial nephritis, a hypercalcemicnephropathy, or a hypokalemic nephropathy.

In some embodiments, the tumor is renal cell carcinoma ornephroblastoma.

In some embodiments, the renal disease is hypertension. In someembodiments, the hypertension is an essential hypertension, hyperpiesa,hyperpiersis, a malignant hypertension, a secondary hypertension, or awhite-coat hypertension.

In some embodiments, the renal disease is a kidney disease.

In some embodiments, the present invention provides methods for treatingor preventing a disorder of glucose metabolism, comprising administeringto a subject in need thereof an effective amount of a compound of theinvention or a composition of the invention. The term “disorder ofglucose metabolism” refers to a disorder that leads to or is manifestedby aberrant glucose storage and/or utilization. To the extent thatindicia of glucose metabolism (i.e. insulin, glucose, or glycatedhemoglobin in a subject's blood plasma or blood serum) are too high, thecompounds of the invention or the compositions of the invention can beadministered to a subject to restore to normal levels. Normal indicia ofglucose metabolism are reported in medical treatises known to those ofskill in the art. See U.S. Pat. No. 7,709,682 B2.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of glucose in a subject's blood plasmaor blood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. An “abnormally high concentration” of glucose in a subject'sblood plasma or blood serum at a fasted state (10-16 hours withouteating) is greater than 5.6 mmol/L (100 mg/dL). In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of glucose is less than 5.6 mmol/L at fasted state. Insome embodiments, a fasted glucose blood plasma or blood serumconcentration in the range of 5.6 mmol/L to 6 mmol/L (100-109 mg/dL) mayindicate prediabetes. In some embodiments, a fasted glucose blood plasmaor blood serum concentration in the range of 6.1 mmol/L to 6.9 mmol/L(110-125 mg/dL) can indicate diabetes. In some embodiments, a fastedglucose blood plasma or blood serum concentration of 7 mmol/L (126mg/dL) and above indicates diabetes.

In some embodiments, the abnormally high concentration of glucose in asubject's blood plasma or blood serum is measured in a glucose tolerancetest (GTT).

An “abnormally high concentration” of glucose in a subject's bloodplasma or blood serum in a one-hour GTT is greater than 10 mmol/L (180mg/dL). In some embodiments, the reducing is to a normal concentration.In some embodiments, the normal concentration in a one-hour GTT is lessthan 10 mmol/L (180 mg/dL).

An “abnormally high concentration” of glucose in a subject's bloodplasma or blood serum in a two-hour GTT with 75 g intake is greater than7.8 mmol/L (140 mg/dL), which indicates hyperglycemia. In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration in two-hour GTT with 75 g intakeis less than 7.8 mmol/L (140 mg/dL). In some embodiments, a glucoseconcentration in a subject's blood plasma or blood serum between 7.8mmol/L (140 mg/dL) and 11.1 mmol/L (200 mg/dL) in two-hour GTT with 75 gintake indicates impaired glucose tolerance. In some embodiments, aglucose concentration above 11.1 mmol/L in two-hour GTT with 75 g intakeindicates diabetes.

In some embodiments, the present invention provides methods forincreasing abnormally low glucose metabolism in a subject, wherein thesubject's glucose concentration in the subject's blood plasma or bloodserum is greater than 7.8 mmol/L (140 mg/dL) in a two-hour GTT. In someembodiments, the present invention provides methods treating orpreventing a disorder of glucose metabolism in a subject, wherein thesubject's glucose concentration in the subject's blood plasma or bloodserum is in the range of 7.8 mmol/L (140 mg/dL) to 11.1 mmol/L (200mg/dL) in a two-hour GTT. In some embodiments, the present inventionprovides methods for treating or preventing a disorder of glucosemetabolism in a subject, wherein the subject's glucose concentration inthe subject's blood plasma or blood serum is greater than 11.1 mmol/L(200 mg/dL) in a two-hour GTT.

In some embodiments, the present invention provides methods for reducingan abnormally high level of HbA_(1c) in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. An “abnormally high level” of hemoglobin A1c (HbA_(1c)) in asubject's blood plasma or blood serum is 6.5% or greater (expressed in %NGSP units). In some embodiments, the reducing is to a normal level. Insome embodiments, the normal levels of HbA_(1c) is in the range of about4% to about 5.9%. In some embodiments, the present invention providesmethods for reducing HbA_(1c) level in a subject's blood plasma or bloodserum, wherein the HbA_(1c) level is greater than 7%, greater than 8%,or greater than 9%. See Horowitz, G. L. et al. Medscape emedicine,updated Jul. 25, 2019.

In some embodiments, the present invention provides methods forincreasing abnormally low glucose metabolism in a subject, wherein thesubject's HbA_(1c) level is 6.5% or greater and the subject's fastingglucose concentration is 126 mg/dL or greater (≥7.0 mmol/L), in thesubject's blood plasma or blood serum. See Selvin, E. et al. Ann InternMed. Published online Jun. 18, 2018.

In some embodiments, the present invention provides methods for treatingor preventing a disorder of glucose metabolism in a subject, wherein thesubject has HbA_(1c) greater than or equal to 6.5%. In some embodiments,the present invention provides methods for treating or preventing adisorder of glucose metabolism in a subject, wherein the subject hasHbA_(1c) greater than or equal to 6.5% and fasting glucose concentrationgreater than or equal to 126 mg/dL (7.0 mmol/L) in the subject's bloodplasma or blood serum.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of glucose in a subject's blood plasmaor blood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention, wherein the subject is pregnant. An “abnormally highconcentration” of glucose in a pregnant subject's blood plasma or bloodserum at fasted state is greater than 5.3 mmol/L (95 mg/dL).

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of glucose in a subject's blood plasmaor blood serum, comprising administering to a subject in need thereof(i) a glucose solution as part of a two-step gestational diabetes testand (ii) an effective amount of a compound of the invention or acomposition of the invention. An “abnormally high concentration” ofglucose in a subject's blood plasma or blood serum at 1 hour afterdrinking the glucose solution in a two-step gestational diabetes test isgreater than 10 mmol/L (180 mg/dL). In the two-step procedure, the firststep is a 50 g glucose dose. If it results in a blood glucose level ofmore than 7.8 mmol/L (140 mg/dL), it is followed by a 100 g glucosedose. An “abnormally high concentration: of glucose in a subject's bloodplasma or blood serum at 2 hour after drinking the glucose solution in atwo-step gestational diabetes test is greater than 8.6 mmol/L (155mg/dL). An “abnormally high concentration: of glucose in a subject'sblood plasma or blood serum at 3 hour after drinking the glucosesolution in a two-step gestational diabetes test is greater than 7.8mmol/L (140 mg/dL).

In some embodiments, the present invention provides methods for treatingor preventing a disorder of glucose metabolism in a subject, wherein thesubject has impaired glucose tolerance. In some embodiments, the presentinvention provides methods for treating or preventing a disorder ofglucose metabolism in a subject, wherein the subject has diabetes. Insome embodiments, the present invention provides methods for treating orpreventing a disorder of glucose metabolism in a subject, wherein thesubject has confirmed undiagnosed diabetes. In some embodiments, thepresent invention provides methods for treating or preventing a disorderof glucose metabolism in a subject, wherein the subject has gestationaldiabetes.

In some embodiments, the present invention provides methods for reducingabnormally high concentration of insulin in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. An “abnormally high concentration” of insulin in a subject'sblood plasma or blood serum at a fasted state is greater than 25 mlU/L(>174 μmol/L). In some embodiments, the reducing is to a normalconcentration. In some embodiments, the normal concentration of insulinin a subject's blood plasma or blood serum at a fasted state is lessthan 25 mlU/L (<174 μmol/L). See Buppajarntham, S. et al. Medscapeemedicine, updated Jan. 2, 2019.

In some embodiments, the present invention provides methods for reducingabnormally high concentration of insulin in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention.

In some embodiments, the methods further comprise administering glucoseto the subject. In some embodiments, the methods do not compriseadministering glucose to the subject. In some embodiments, the subjectis in a fasted state.

In some embodiments, the subject has an abnormally concentration ofinsulin in the subject's blood plasma or blood glucose at 30 minutesafter glucose administration. An “abnormally high concentration” ofinsulin in a subject's blood plasma or blood serum at 30 minutes afterglucose administration is greater than 230 mlU/L (>1597 μmol/L). In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of insulin in a subject's bloodplasma or blood serum at 30 minutes after glucose administration is inthe range of about 30 mlU/L to about 230 mlU/L (208-1597 μmol/L). SeeBuppajarntham, 2019.

In some embodiments, the subject has an abnormally concentration ofinsulin in the subject's blood plasma or blood serum at 1 hour afterglucose administration. An “abnormally high concentration” of insulin ina subject's blood plasma or blood serum at 1 hour after glucoseadministration is greater than 276 mlU/L (>1917 μmol/L). In someembodiments, the present invention provides methods for reducingabnormally high concentration of insulin in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the reducing is to a normalconcentration. In some embodiments, the normal concentration of insulinin a subject's blood plasma or blood serum at 1 hour after glucoseadministration is in the range of about 18 mlU/L to about 276 mlU/L(125-1917 μmol/L). See Buppajarntham, 2019.

In some embodiments, the subject has an abnormally concentration ofinsulin in the subject's blood plasma or blood glucose at 2 hours afterglucose administration. An “abnormally high concentration” of insulin ina subject's blood plasma or blood serum at 2 hour after glucoseadministration is greater than 166 mlU/L (>1153 μmol/L). In someembodiments, the present invention provides methods for reducing anabnormally high concentration of insulin in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the normal concentration of insulin in asubject's blood plasma or blood serum at 2 hours after glucoseadministration is in the range of about 16 mlU/L to about 166 mlU/L(111-1153 μmol/L). See Buppajarntham, 2019.

In some embodiments, the subject has an abnormally concentration ofinsulin in the subject's blood plasma or blood glucose at 3 hours afterglucose administration. An “abnormally high concentration” of insulin ina subject's blood plasma or blood serum at 3 hours after glucoseadministration is greater than 25 mlU/L (>174 μmol/L). In someembodiments, the present invention provides methods for reducing anabnormally high concentration of insulin in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the normal concentration of insulin in asubject's blood plasma or blood serum at 3 hours or later after glucoseadministration is less than 25 mlU/L (<174 μmol/L). See Buppajarntham,2019.

In some embodiments, the present invention provides methods for treatingor preventing a disorder of glucose metabolism in a subject, wherein thesubject has insulin concentration in the subject's blood plasma or bloodserum above 25 mlU/L at a fasted state or after 3 hours after glucoseadministration. See Buppajarntham, 2019.

In some embodiments, the disorder of glucose metabolism is an impairedglucose tolerance; an insulin resistance; an insulin resistance-relatedbreast, colon or prostate cancer; diabetes; pancreatitis; hypertension;polycystic ovarian disease; or an abnormally high concentration of bloodinsulin or glucose in the subject's blood plasma or blood serum. In someembodiments, the diabetes is non-insulin dependent diabetes mellitus(NIDDM), insulin dependent diabetes mellitus (IDDM), gestationaldiabetes mellitus (GDM), or maturity onset diabetes of the young (MODY).

In some embodiments, the present invention provides methods for treatingor preventing a metabolic syndrome (syndrome X), comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. In someembodiments, the present invention provides methods for treating orpreventing a symptom of a metabolic syndrome (syndrome X), comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. In someembodiments, the symptom is impaired glucose tolerance, hyper tension,dyslipidemia, or dyslipoproteinemia.

In some embodiments, the present invention provides methods for treatingor preventing a vascular disease or cardiovascular disease, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. The term“cardiovascular disease” refers to a disease of the heart or circulatorysystem. In some embodiments, the vascular disease or the cardiovasculardisease is a peripheral vascular disease, a coronary heart disease,stroke, restenosis, arteriosclerosis, ischemia, an endotheliumdysfunction, an ischemia-reperfusion injury, a myocardial infarction, ora cerebral infarction.

In some embodiments, the present invention provides methods for treatingor preventing a PPAR-associated disorder, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thePPAR-associated disorder is rheumatoid arthritis, multiple sclerosis,psoriasis, an inflammatory bowel disease, breast cancer, colon cancer,or prostate cancer. In some embodiments, the PPAR-associated disorder isa vascular disease, a muscular disease, a demyelinating disease, amuscle structure disorder, a neuronal activation disorder, a musclefatigue disorder, a muscle mass disorder, a mitochondrial disease, amitochondrial dysfunction, a beta oxidation disease, or a metabolicdisease. In some embodiments, the PPAR-associated disorder is anabnormally low concentration of HDL, an abnormally low concentration ofapolipoprotein A-I (apo A-I), an abnormally high concentration ofVLDL-C, an abnormally high concentration of low density lipoproteincholesterol (LDL-C), an abnormally high concentration of triglyceride,an abnormally high concentration of apolipoprotein B (apo B), anabnormally high concentration of apolipoprotein C-III (apo C-III) or anabnormally reduced ratio of post-heparin hepatic lipase to lipoproteinlipase activity in the subject's blood plasma or blood serum. In someembodiments, the PPAR-associated disorder is an abnormally highconcentration of HDL or an abnormally low concentration of apo A-I inthe subject's lymph or cerebral fluid.

In some embodiments, the PPAR-associated disorder is abnormally lowconcentration of lipoprotein lipase activity in the post-heparin plasmain a subject (subject's blood plasma after intravenous injection ofheparin). In some embodiments, the present invention provides methodsfor elevating an abnormally low concentration of lipoprotein lipaseactivity in the post-heparin plasma, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. An “abnormally lowconcentration” of lipoprotein lipase activity in the post-heparin plasmais less than 30 U/L. In some embodiments, the elevating is to a normalconcentration. In some embodiments, the normal concentration is in therange from about 30 U/L to about 153 U/L (See Nakajima et al. Clin ChimActa. 2018 December; 487:54-59).

In some embodiments, the present invention provides methods for treatingor preventing a PPAR-associated disorder in a subject, wherein thesubject has lipoprotein lipase activity in the post-heparin plasma ofless than 30 U/L.

In some embodiments, the subject is a male subject. An “abnormally highconcentration” of HDL in a male subject is greater than 75 mg/dL.

In some embodiments, the subject is a female subject. An “abnormallyhigh concentration” of HDL for a female subject is greater than 90mg/dL.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of HDL in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the reducing is to a normalconcentration. In some embodiments, the normal concentration for a malesubject is less than 75 mg/dL. In some embodiments, the normalconcentration for a female subject is less than 90 mg/dL. In someembodiments, the present invention provides methods for treating orpreventing a PPAR-associated disorder in a male subject, wherein thesubject has HDL concentration in the subject's blood plasma or bloodserum greater than 75 mg/dL. In some embodiments, the present inventionprovides methods for treating or preventing a PPAR-associated disorderin a female subject, wherein the subject has HDL concentration in thesubject's blood plasma or blood serum greater than 90 mg/dL. See Hassan,M. et. al. Glob Cardiol Sci Pract. 2016 Dec. 30; 2016(4): e201634.

In some embodiments, the muscular disease is a muscular dystrophydisease. In some embodiments, the muscular dystrophy disease is Duchennemuscular dystrophy, Becker muscular dystrophy, a limb-girdle musculardystrophy, congenital muscular dystrophy, facioscapulohumeral musculardystrophy, myotonic muscular dystrophy, oculopharyngeal musculardystrophy, distal muscular dystrophy, or Emery-Dreifuss musculardystrophy.

In some embodiments, the demyelinating disease is multiple sclerosis,Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease,encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, orGuillian-Barre syndrome.

In some embodiments, the muscle structure disorder is Bethlem myopathy,central core disease, congenital fiber type disproportion, distalmuscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD,facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a musclesodium channel disorder, myotonic chondrodystrophy, myotonic dystrophy,myotubular myopathy, nemaline body disease, oculopharyngeal MD, orstress urinary incontinence.

In some embodiments, the neuronal activation disorder is amyotrophiclateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome,Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, a nervelesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnarnerve palsy, or toxic myoneural disorder.

In some embodiments, the muscle fatigue disorder is chronic fatiguesyndrome, diabetes (type I or II), a glycogen storage disease,fibromyalgia, Friedreich's ataxia, intermittent claudication, lipidstorage myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis,and stroke-like episodes) syndrome, mucopolysaccharidosis, Pompedisease, or thyrotoxic myopathy.

In some embodiments, the muscle mass disorder is cachexia, cartilagedegeneration, cerebral palsy, compartment syndrome, critical illnessmyopathy, inclusion body myositis, muscular atrophy (disuse),sarcopenia, steroid myopathy, or systemic lupus erythematosus.

In some embodiments, the mitochondrial disease is Alpers's disease,chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayrasyndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS,myoclonic epilepsy and ragged-red fiber disease (MERRF), neurogenicmuscle weakness (NARP), ataxia, retinitis pigmentosa, Pearson syndrome,a mitochondrial malfunction, or a mitochondrial loss of functionality(for example, due to a drug affecting mitochondrial functions).

In some embodiments, the mitochondrial dysfunction is a drug inducedmitochondrial dysfunction.

In some embodiments, the beta oxidation disease is systemic carnitinetransporter, carnitine palmitoyltransferase (CPT) II deficiency, verylong-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency,trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase(MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency,or riboflavin-responsive disorders of p-oxidation (RR-MADD).

In some embodiments, the metabolic disease is hyperlipidemia,dyslipidemia, hyperchlolesterolemia, hypertriglyceridemia, HDLhypocholesterolemia, LDL hypercholesterolemia, HLD non-cholesterolemia,VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-1hypoproteinemia, atherosclerosis, a disease of arterial sclerosis, adisease of cardiovascular system, cerebrovascular disease, peripheralcirculatory disease, metabolic syndrome, syndrome X, obesity, diabetes,type I diabetes, type II diabetes, hyperglycemia, insulin resistance,impaired glucose tolerance, hyperinsulinism, a diabetic complication,cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension,non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), a thrombus, Alzheimer disease, a neurodegenerative disease, ademyelinating disease, multiple sclerosis, adrenal leukodystrophy,dermatitis, psoriasis, acne, skin aging, trichosis, inflammation,arthritis, asthma, hypersensitive intestine syndrome, ulcerativecolitis, Crohn's disease, or pancreatitis.

In some embodiments, the present invention provides methods for treatingor preventing septicemia, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, septicemia is septicshock.

In some embodiments, the present invention provides methods for treatingor preventing a thrombotic disorder, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thethrombotic disorder is high concentration of fibrinogen in the subject'sblood plasma or blood serum, or promotion of fibrinolysis.

In some embodiments, the present invention provides methods for treatingor preventing obesity, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the obesity isabdominal obesity. In some embodiments, the methods for treating orpreventing obesity further comprise promoting weight reduction in thesubject.

In some embodiments, the present invention provides methods for treatingor preventing diabetic nephropathy, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, themethods for treating or preventing diabetic nephropathy further comprisetreating or preventing a kidney disease that develops as a result ofdiabetes mellitus. In some embodiments, the present invention providesmethods for treating or preventing diabetes mellitus, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention.

In some embodiments, the present invention provides methods for treatingor preventing diabetic retinopathy, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, themethods for treating or preventing diabetic retinopathy result intreating or preventing a complication of diabetes that can lead to orcause blindness.

In some embodiments, the present invention provides methods for treatingor preventing a cerebrovascular disease, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thecerebrovascular disease is cerebral ischemia.

In some embodiments, the present invention provides methods for treatingor preventing a disorder related to neovascularization, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. In someembodiments, the disorder related to neovascularization is retinopathyor diabetes.

In some embodiments, the present invention provides methods for treatingor preventing hypertension, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the methods fortreating or preventing hypertension result in treating or preventingblood flow that occurs through the subject's vessels at a greater thannormal force.

In some embodiments, the present invention provides methods for treatingor preventing cancer, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the cancer is a humansarcoma or human carcinoma. In some embodiments, the cancer isfibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,bone cancer, breast cancer, ovarian cancer, prostate cancer, esophagealcancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinoma,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acutelymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia,acute promyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocytic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, hairy cellleukemia, lymphoblastic leukemia, myelogenous leukemia,lymphocyticleukemia, myelocytic leukemia, polycythemia vera, multiplemyeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma,Waldenstrom's macroglobulinemia, or a heavy chain disease.

In some embodiments, the leukemia is acute or chronic lymphoblasticleukemia, myelogenous leukemia, lymphocyticleukemia, lymphocyticleukemia, or myelocytic leukemia. In some embodiments, the myelocyticleukemia is acute and is myeloblastic, promyclocytic, myelomonocytic,monocytic or erythroleukemia

In some embodiments, the lymphoma is Hodgkin's lymphoma or non-Hodgkin'slymphoma.

In some embodiments, the present invention provides methods for treatingor preventing an inflammatory disease, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, theinflammatory disease is multiple sclerosis, a chronic inflammatorydisorder of a joint, arthritis, a respiratory distress syndrome, aninflammatory bowel disease, an inflammatory lung disorder, aninflammatory disorder, an inflammatory disorder of the gum,tuberculosis, leprosy, an inflammatory disease of the kidney, aninflammatory disorder of the skin, an inflammatory disease of thecentral nervous system, a systemic lupus erythematosus (SLE) or aninflammatory disease of the heart.

In some embodiments, the arthritis is rheumatoid arthritis orosteoarthritis.

In some embodiments, the inflammatory bowel disease is ileitis,ulcerative colitis or Crohn's disease.

In some embodiments, the inflammatory lung disorder is asthma or chronicobstructive airway disease.

In some embodiments, the inflammatory disorder of the eye is cornealdystrophy, trachoma, onchocerciasis, uveitis, sympathic ophthalmitis orendophthalmitis.

In some embodiments, the inflammatory disorder of the gum isperiodontitis or gingivitis.

In some embodiments, the inflammatory disease of the kidney isglomerulonephritis or nephrosis.

In some embodiments, the inflammatory disorder of the skin is acne,sclerodermatitis, psoriasis, eczema, photoaging or wrinkles.

In some embodiments, the inflammatory disease of the central nervoussystem is AIDS-related neurodegeneration, stroke, neurotrauma,Alzheimer's disease, encephalomyelitis, or viral or autoimmuneencephalitis.

In some embodiments, the inflammatory disease of the heart iscardiomyopathy.

In some embodiments, the present invention provides methods for treatingor preventing a neurodegenerative disease, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, theneurodegenerative disease is Alzheimer's disease or Huntington'sdisease.

In some embodiments, the present invention provides methods for treatingor preventing an autoimmune disease, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, theautoimmune disease is immune-complex vasculitis, systemic lupus orerythematodes.

In some embodiments, the present invention provides methods for treatingor preventing a neoplastic disease, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, theneoplastic disease is carcinogenesis.

In some embodiments, the present invention provides methods for treatingor preventing cholestasis, comprising administering to a subject in needthereof an effective amount of the compound of the invention or thecomposition of the invention.

In some embodiments, the cholestasis is intrahepatic cholestatic diseaseor extrahepatic cholestatic disease. In some embodiments, theintrahepatic cholestatic disease is primary biliary cholangitis (PBC),primary sclerosing cholangitis (PSC), progressive familial intrahepaticcholestasis (PFIC), or Alagille syndrome (AS). In some embodiments, themethods for treating or preventing intrahepatic cholestatic diseaseresult in preventing or reducing the risk of developing an intrahepaticcholestatic disease, e.g., causing the clinical symptoms of an intrahepatic cholestatic disease to not develop in a subject who may bepredisposed to an intrahepatic cholestatic disease by who does not yetexperience or display symptoms of the intrahepatic cholestatic disease(i.e., prophylaxis). In some embodiments, the methods for treating orpreventing intrahepatic cholestatic disease comprise inhibiting anintrahepatic cholestatic disease, e.g., arresting or reducing thedevelopment of the intrahepatic cholestatic disease or reducing thenumber, frequency, duration or severity of one or more of its clinicalsymptoms.

In some embodiments, the present invention provides methods for treatingor preventing an ocular disease, comprising administering to a subjectin need thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the ocular disease isdry eye, meibomian gland dysfunction, a keratoconjunctiva epithelialdisorder, a corneal epithelial disorder, or a corneal ulcer. In someembodiments, the ocular disease is dry eye syndrome, corneal ulcer,superficial punctuate keratitis, corneal epithelial erosion, an ocularallergic disease associated with corneal lesion such as vernalconjunctivitis, or atopic keratoconjunctivitis. In some embodiments, theocular disease is hyperevaporative dry eye. In some embodiments, theocular disease is injury of corneal epithelial cells. In someembodiments, the injury of corneal epithelial cells is associated withendogenous diseases such as Sjogren's syndrome, Stevens-Johnsonsyndrome, keratoconjunctivitis sicca (dry eye) or the like. In someembodiments, the injury of corneal epithelial cells is associated withexogenous diseases such as post-operation, drug use, trauma, cornealulcer, meibomianitis, exogenous diseases during wearing contact lensesor the like. In some embodiments, the injury of corneal epithelial cellsis associated with ocular allergic diseases accompanying corneal lesionsuch as vernal conjunctivitis, atopic keratoconjunctivitis or the like.In some embodiments, the ocular disease is superficial punctuatekeratitis and corneal epithelial erosion.

In some embodiments, the methods for treating or preventing an oculardisease result in promoting proliferation of meibomian gland epithelialcells and corneal epithelial cells.

In some embodiments, the present invention provides methods for treatingor preventing a lysosomal storage disorder, comprising administering toa subject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thelysosomal storage disorder is neuronal ceroid lipofuscinosis,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS), Parkinson's disease, multiple system atrophy (MSA), progressivesupranuclear palsy (PSP), corticobasal degeneration (CBD), dementia withLewy bodies (DLB), a disorder of the autophagy pathway, Tay-Sach'sdisease, Fabry disease, Niemann-Pick disease, Gaucher disease, Huntersyndrome, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl esterstorage disease, chronic hexosaminidase A deficiency, cystinosis, Danondisease, Farber disease, fucosidosis, galactosialidosis, or Battendisease.

In some embodiments, the present invention provides methods for treatingor preventing a kidney disease, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the kidney disease isrenal ischemia reperfusion injury. In some embodiments, the kidneydisease is acute kidney injury. In some embodiments, the methods fortreating or preventing a kidney disease result in lowering the subject'srisk for acute kidney injury following coronary artery bypass graft,transplantation, and/or valve surgery.

In some embodiments, the subject has AKI. In other embodiments, thesubject is at risk for AKI.

AKI can be characterized by rapid decline in renal functions, which canbe caused by a number of factors, such as a reduction in renal bloodflow, glomerulonephritis, use of nephrotoxic antibiotics, use ofanticancer agents, and sepsis.

Acute kidney injury can be diagnosed, for example, when a subjectexhibits changes in one or more of serum creatinine level, glomerularfiltration rate, or urine output. For example, AKI can be characterizedby a serum creatinine level of at least 1.5 times baseline, whereinbaseline refers to the subject's serum creatinine level no more than 7days prior. For example, a patient having AKI can have a serumcreatinine level is 1.5 to 1.9 times baseline, 2.0 to 2.9 timesbaseline, or 3.0 or more times baseline. Alternatively, AKI can becharacterized by an increase in serum creatinine of at least 0.3 mg/dLor at least 0.4 mg/dL, for example by an increase of serum creatinine ofat least 0.3 mg/dL within a 48 hour period.

Alternatively, AKI can be characterized by a glomerular filtration rateof less than 90 mL/min/1.73 m². For example, a subject having AKI canhave glomerular filtration rate of 60-89 mL/min/1.73 m², 30-59mL/min/1.73 m², 15-29 mL/min/1.73 m², or less than 15 mL/min/1.73 m².

Alternatively, AKI can be characterized by a subject having a urineoutput of less than 0.5 mL/Kg over 6 hours, less than 0.5 mL/Kg over 12hours, less than 0.3 mL/Kg over 12 hours, or anuria for 12 or morehours.

AKI can be classified using the KDIGO criteria (Kidney Disease ImprovingGlobal Outcomes. KDIGO Clinical Practice Guideline for Acute KidneyInjury. Kidney International Supplements 2012; 2:1-138) shown in Table12.

TABLE 12 KDIGO classification for AKI Stage Serum creatinine Urineoutput 1 1.5-1.9 times baseline <0.5 ml/kg/h for 6-12 hours OR ≥0.3mg/dl (≥26.5 μmol/l) increase 2 2.0-2.9 times baseline <0.5 ml/kg/h for≥12 hours 3 3.0 times baseline <0.3 ml/kg/h for ≥24 hours OR OR Increasein serum creatinine to ≥4.0 Anuria for ≥12 hours mg/dl (≥353.6 μmol/l)OR Initiation of renal replacement therapy OR, in patients <18 years,decrease in eGFR to <35 ml/min per 1.73 m³

AKI can occur with specific kidney diseases (e.g., acute interstitialnephritis, acute glomerular and vasculitic renal diseases); non-specificconditions (e.g., ischemia, toxic injury); as well as extrarenalpathology (e.g., prerenal azotemia, and acute postrenal obstructivenephropathy). More than one of these conditions may coexist in the samesubject and, more importantly, epidemiological evidence supports thenotion that even mild, reversible AKI has important clinicalconsequences, including increased risk of death. Furthermore, becausethe manifestations and clinical consequences of AKI can be quite similar(even indistinguishable) regardless of whether the etiology ispredominantly within the kidney or predominantly from outside stresseson the kidney, AKI encompasses both direct injury to the kidney as wellas acute impairment of function.

In some embodiments, the subject having AKI or at risk of AKI hasdiabetes, underlying renal insufficiency, nephritic syndrome,atherosclerotic disease, sepsis, hypotension, hypoxia,myoglobinuria-hematuria, or liver disease. In some embodiments, thesubject is elderly, pregnant, a surgical patient, or has been exposed toa nephrotoxic agent. In a specific embodiment, the subject having AKI orat risk of AKI is a surgical patient. Accordingly, in certainembodiments, a compound of the disclosure is administered to a surgicalpatient after surgery, e.g., after a cardiovascular procedure such ascoronary artery bypass graft (CABG) surgery and/or heart valve surgery.

In some embodiments, the subject has sepsis (e.g., associated with agram-negative bacterial infection). The sepsis can in some embodimentsbe caused by an intra-abdominal cavity infection or be urosepsis. Sepsisis a risk factor for AKI. Thus, in some embodiments, the subject can beat risk for AKI, for example due to sepsis.

In some embodiments, the subject has a shortened sequential organfailure assessment score (SOFA) score of 1 to 4 before treatment with acompound of the disclosure, e.g., a score of 1, 2, 3, or 4 (see, Vincentet al. 1996, Intensive Care Med, 22:707-710).

In some embodiments, the subject has AKI secondary to an infection or isat risk of AKI due to an infection, for example a viral infection, e.g.,COVID-19.

In some embodiments, the subject having AKI or at risk of AKI has beenexposed to a nephrotoxic agent. A nephrotoxic agent is a drug orchemical capable of causing AKI. Drugs or chemicals capable of causingAKI include, but are not limited to, cisplatin; gentamicin;cephaloridine; cyclosporine; amphotericin; carbon tetrachloride;trichloroethylene; and dichloroacetylene.

In some embodiments, the present invention provides methods for treatingor preventing impotence, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. In some embodiments, the impotence resultsfrom damages to a nerve, artery, smooth muscles, or fibrous tissue;diabetes; kidney disease; alcoholism; multiple sclerosis;atherosclerosis; vascular disease; or neurologic disease. In someembodiments, the methods for treating or preventing impotence results intreating or preventing erectile dysfunction.

The present invention provides methods for treating or preventinghyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. In someembodiments, the hypercholesterolemia is homozygous familialhypercholesterolemia.

The present invention provides methods for treating a subject having orpreventing a subject from having an abnormally high concentration in asubject's blood plasma or blood serum of high low-density lipoprotein(LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)), apolipoprotein(a), or very low-density lipoprotein (VLDL), comprising administering toa subject in need thereof an effective amount of a compound of theinvention or a composition of the invention.

An “abnormally high concentration” of lipoprotein-cholesterol can dependon the number of risk factors and whether the treatment is for a primaryor a secondary prevention. As used herein a “primary prevention” refersto a treatment aimed to avoid a subject developing or getting a diseaseor a condition. As used herein a “secondary prevention” refers to atreatment aimed to detect a disease or a condition early and prevent thedisease or condition from getting worse or advancing. Recommendedlipoprotein-cholesterol concentrations can be found in guidelinespublished by the National Lipid Association or by the National Instituteof Health National Heart, Lung, and Blood Institute such as the ThirdReport of the Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults (ATP III Final Report), 2002. The ATPIII Final Report is hereby incorporated by reference in its entirety forall purposes.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of apo B in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, an “abnormally high concentration” ofapo B in a subject's blood plasma or blood serum is greater than 130mg/dL. In some embodiments, the reducing is to a normal concentration.In some embodiments, the normal concentration of apo B in a subject'sblood plasma or blood serum is less than 130 mg/dL. In some embodiments,the subject is a male subject. In some embodiments, the subject is afemale subject. In some embodiments, the present invention providesmethods for treating a subject with apo B blood plasma or blood serumconcentration of greater than 130 mg/dL. In some embodiments, thepresent invention provides methods for treating a subject with apo Bblood plasma or blood serum concentration of greater than 130 mg/dL,when the subject is at low risk of coronary heart disease (CHD) having0-1 CHD risk factors.

In some embodiments, the present invention provides methods for treatinga subject with apo B blood plasma or blood serum concentration ofgreater than 110 mg/dL, when the subject is at moderate risk of CHDhaving 2 or more CHD risk factors. In some embodiments, an “abnormallyhigh concentration” of apo B in a subject's blood plasma or blood serumis greater than 110 mg/dL. In some embodiments, the subject has 2 ormore CHD risk factors. In some embodiments, the subject has a CHD or aCHD risk equivalent. In some embodiments, the present invention providesmethods for treating a subject with apo B blood plasma or blood serumconcentration of greater than 90 mg/dL, when the subject has a CHD or aCHD risk equivalent.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of Lp(a) in a subject's blood plasma orblood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. An “abnormally high concentration” of Lp(a) in a subject'sblood plasma or blood serum is greater than 10 mg/dL. In someembodiments, the abnormally high concentration of Lp(a) is associatedwith an increase in cardiovascular risk. In some embodiments, thereducing is to a normal concentration. In some embodiments, the normalconcentration of Lp(a) in a subject's blood plasma or blood serum isless than 10 mg/dL. In some embodiments, the normal concentration ofLp(a) in a subject's blood plasma or blood serum is less than 50 mg/dL(See, Banach, M. J Am Heart Assoc. 2016 April; 5(4): e003597). In someembodiments, the present invention provides methods for treating asubject with Lp(a) blood plasma concentration of greater than 50 mg/dL,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

The present invention provides methods for treating a subject having orpreventing a subject from having an abnormally high apo B/apo A-1 ratioin a subject's blood plasma or blood serum, comprising administering toa subject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thepresent invention provides methods for reducing an abnormally high apoB/apo A-1 ratio in a subject's blood plasma or blood serum, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. An“abnormally high” apo B/apo A-1 ratio in a subject's blood plasma orblood serum is greater than 0.9. In some embodiments, the reducing is toa normal level. In some embodiments, a normal apo B/apo A-1 ratio in asubject's blood plasma or blood serum is less than 0.9. In someembodiments, the normal apo B/apo A-1 ratio in a subject's blood plasmaor blood serum is less than 0.7. In some embodiments, the subject has anapo B/apo A-1 ratio in a subject's blood plasma or blood serum ofgreater than 0.9. In some embodiments, the subject has an apo B/apo A-1ratio in a subject's blood plasma or blood serum of greater than 0.7.See Walldius, G. et al. J Intern Med. 2006 May; 259(5):493-519.

In some embodiments, a male subject having an apo B/apo A-1 ratio in themale subject's blood plasma or blood serum of greater than 0.9 isconsidered for a primary prevention treatment. In some embodiments, afemale subject having an apo B/apo A-1 ratio in the female subject'sblood plasma or blood serum of greater than 0.8 is considered for aprimary prevention treatment. In some embodiments, the subject is a malesubject and has an apo B/apo A-1 ratio in the subject's blood plasma orblood serum of greater than 0.9. In some embodiments, the subject is afemale subject and has an apo B/apo A-1 ratio in the subject's bloodplasma or blood serum of greater than 0.8. See Walldius, 2006.

In some embodiments, a male subject having an apo B/apo A-1 ratio in themale subject's blood plasma or blood serum of greater than 0.7 isconsidered for a secondary prevention treatment. In some embodiments, afemale subject having an apo B/apo A-1 ratio in the female subject'sblood plasma or blood serum of greater than 0.6 is considered for asecondary prevention treatment. In some embodiments, the subject is amale subject and has an apo B/apo A-1 ratio in the subject's bloodplasma or blood serum of greater than 0.7. In some embodiments, thesubject is a female subject and has an apo B/apo A-1 ratio in thesubject's blood plasma or blood serum of greater than 0.6. See Walldius,2006.

The present invention provides methods for treating a subject having orpreventing a subject from having an abnormally low concentration in asubject's blood plasma or blood serum of high-density lipoprotein (HDL),comprising administering to a subject in need thereof an effectiveamount of the compound of the invention or the composition of theinvention.

The present invention provides methods for treating a subject having orpreventing a subject from having an abnormally reduced or deficientlipoprotein lipase concentration or activity in a subject's blood plasmaor blood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the reduced or deficient lipoproteinlipase level or activity is a result of a lipoprotein lipase mutation.In some embodiments, the reduced or deficient lipoprotein lipase levelor activity is a result of a mutation in a gene encoding a lipoproteinlipase.

In some embodiments, the present invention provides methods forelevating an abnormally low concentration of lipoprotein lipase in asubject's blood plasma or blood serum, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or a composition of the invention. An “abnormally reducedconcentration” of lipoprotein lipase in a subject's blood serum is lessthan 46 ng/mL. In some embodiments, the subject has an increased riskfor future coronary artery disease. In some embodiments, the elevatingis to a normal concentration. In some embodiments, the normalconcentration of lipoprotein lipase in a subject's blood serum isgreater than 46 ng/mL. In some embodiments, the present inventionprovides methods for treating a subject with lipoprotein lipase bloodplasma or blood serum concentration of less than 46 ng/mL, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. See Rip, J.et al. Arterioscler Thromb Vasc Biol. 2006 March; 26(3):637-42. Epub2005 Dec. 22.

The present invention provides methods for treating a subject having orpreventing a subject from having an abnormally high concentration oflipoprotein-associated phospholipase A₂ (Lp-PLA₂) in a subject's bloodplasma or blood serum, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention. An “abnormally high concentration” ofLp-PLA₂ in a subject's blood plasma or blood serum is greater than 200ng/mL. In some embodiments, the subject has a risk for developingcardiovascular disease. In some embodiments, the risk is high.

In some embodiments, the present invention provides methods for reducingan abnormally high concentration of Lp-PLA₂ in a subject's blood plasmaor blood serum, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the reducing is to a normalconcentration. In some embodiments, the normal concentration of Lp-PLA₂in a subject's blood plasma or blood serum concentration is less than200 ng/mL. In some embodiments, the present invention provides methodsfor treating a subject with Lp-PLA₂ blood plasma or blood serumconcentration of greater than 200 ng/mL. See Davidson, M. H. et al, TheAmerican Journal of Cardiology, 2008, 101, S51.

The present invention provides methods for treating or preventinghypoalphalipoproteinemia, a lipoprotein abnormality associated withdiabetes, a lipoprotein abnormality associated with obesity, alipoprotein abnormality associated with Alzheimer's Disease, or familialcombined hyperlipidemia, comprising administering to a subject in needthereof an effective amount of a compound of the invention or acomposition of the invention.

The present invention provides methods for reducing in a subject's bloodplasma or blood serum an abnormally high concentration of triglyceride,low-density lipoprotein cholesterol (LDL-C), very low-densitylipoprotein cholesterol (VLDL-C), non-high-density lipoproteincholesterol, (non-HDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B,HDL/(VLDL+LDL) ratio, apolipoprotein C-II (apo C-II) or apolipoproteinC-III (apo C-III), comprising administering to a subject in need thereofan effective amount of a compound of the invention or a composition ofthe invention.

An “abnormally high concentration” of triglyceride in a subject's bloodserum is greater than 150 mg/dL. In some embodiments, the reducing is toa normal concentration. In some embodiments, the normal concentration oftriglyceride in a subject's blood serum is less than 150 mg/dL. In someembodiments, the present invention provides methods for reducing asubject's blood serum triglyceride concentration, where the subject hasa blood serum triglyceride concentration greater than or equal to 200mg/dL. In some embodiments, the present invention provides methods forreducing a subject's blood serum triglyceride concentration, where thesubject has a blood serum triglyceride concentration greater than orequal to 500 mg/dL.

An “abnormally high concentration” of LDL-C in a subject's blood plasmaor blood serum for primary prevention is greater than 100 mg/dL. An“abnormally high concentration” of LDL-C in a subject's blood plasma orblood serum for secondary prevention in a subject with risk factors isgreater than 70 mg/dL. In some embodiments, the reducing is to a normalconcentration. In some embodiments, the normal concentration of LDL-C ina subject's blood plasma or blood serum is less than 100 mg/dL, whereinthe subject is being considered for primary prevention. In someembodiments, the normal concentration of LDL-C in a subject's bloodplasma or blood serum is less than 70 mg/dL. In some embodiments, thesubject has risk factors and is being considered for secondaryprevention. See Walldius, 2006.

In some embodiments, an “abnormally high concentration” of LDL-C in asubject's blood plasma or blood serum is greater than 160 mg/dL. In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of LDL-C in a subject's bloodplasma or blood serum is less than 160 mg/dL. In some embodiments, thesubject has 0-1 CHD risk factors. In some embodiments, the presentinvention provides methods for treating a subject with LDL-C bloodplasma or blood serum concentration of greater than 160 mg/dL. In someembodiments, the present invention provides methods for treating asubject with LDL-C blood plasma or blood serum concentration of greaterthan 160 mg/dL. In some embodiments, the subject has 0-1 CHD riskfactors. See Walldius, 2006.

In some embodiments, an “abnormally high concentration” of LDL-C in asubject's blood plasma or blood serum is greater than 130 mg/dL. In someembodiments, the subject has 2 or more CHD risk factors. In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of LDL-C in a subject's bloodplasma or blood serum is less than 130 mg/dL. In some embodiments, thesubject has 2 or more CHD risk factors. In some embodiments, the presentinvention provides methods for treating a subject with LDL-C bloodplasma or blood serum concentration of greater than 130 mg/dL. In someembodiments, the subject has 2 or more CHD risk factors. See Walldius,2006.

In some embodiments, an “abnormally high concentration” of LDL-C in asubject's blood plasma or blood serum is greater than 100 mg/dL. In someembodiments, the subject has a CHD or a CHD risk equivalent. In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of LDL-C in a subject's bloodplasma or blood serum is less than 100 mg/dL. In some embodiments, thesubject has a CHD or a CHD risk equivalent. In some embodiments, thepresent invention provides methods for treating a subject with LDL-Cblood plasma or blood serum concentration of greater than 100 mg/dL. Insome embodiments, the subject has a CHD or a CHD risk equivalent. SeeWalldius, 2006.

An “abnormally high concentration” of apo C-III concentration in asubject's blood plasma or blood serum is greater than 7.87 mg/dL. Insome embodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of apo C-III concentration in asubject's blood plasma or blood serum is less than 7.87 mg/dL. In someembodiments, the present invention provides methods for treating asubject, where the subject has an apo C-III blood plasma or blood serumconcentration greater than 8 mg/dL. In some embodiments, the presentinvention provides methods for treating a subject, where the subject hasan apo C-III blood plasma or blood serum concentration greater than 7.9mg/dL. In some embodiments, the present invention provides methods fortreating a subject, where the subject has an apo C-III blood plasma orblood serum concentration greater than 7.87 mg/dL. In some embodiments,the abnormally high concentration of apo C-III is associated with highrisk of coronary artery disease. See Capelleveen et al. ArteriosclerThromb Vasc Biol. 2017 June; 37(6): 1206-1212.

The present invention provides methods for reducing in a subject's bloodplasma or blood serum an abnormally high LDL-C/HDL-C ratio, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention.

In some embodiments, an “abnormally high ratio” of LDL-C/HDL-C in a malesubject's blood plasma or blood serum for primary prevention is greaterthan 3.0. In some embodiments, the reducing is to a normal ratio. Insome embodiments, the normal ratio of LDL-C/HDL-C in a male subject'sblood plasma or blood serum is less than 3.0, wherein the subject isbeing considered for primary prevention. In some embodiments, thepresent invention provides methods for treating a male subject with anLDL-C/HDL-C ratio in a subject's blood plasma or blood serum of greaterthan 3.0. In some embodiment, the me method is for primary prevention.

In some embodiments, an “abnormally high ratio” of LDL-C/HDL-C in afemale subject's blood plasma or blood serum for primary prevention isgreater than 2.5. In some embodiments, the reducing is to a normalratio. In some embodiments, the normal ratio of LDL-C/HDL-C in a femalesubject's blood plasma or blood serum is less than 2.5, wherein thesubject is being considered for primary prevention. In some embodiments,the present invention provides methods for treating a female subjectwith an LDL-C/HDL-C ratio in a subject's blood plasma or blood serum ofgreater than 2.5. In some embodiment, the me method is for primaryprevention. See Walldius, 2006.

In some embodiments, an “abnormally high ratio” of LDL-C/HDL-C in a malesubject's blood plasma or blood serum for secondary prevention isgreater than 2.5. In some embodiments, the reducing is to a normalratio. In some embodiments, the normal ratio of LDL-C/HDL-C in a malesubject's blood plasma or blood serum is less than 2.5, wherein thesubject is being considered for secondary prevention. In someembodiments, the present invention provides methods for treating a malesubject with an LDL-C/HDL-C ratio in a subject's blood plasma or bloodserum of greater than 2.5. In some embodiment, the me method is forsecondary prevention. See Walldius, 2006.

In some embodiments, an “abnormally high ratio” of LDL-C/HDL-C in afemale subject's blood plasma or blood serum for secondary prevention isgreater than 2.0. In some embodiments, the reducing is to a normalratio. In some embodiments, the normal ratio of LDL-C/HDL-C in a femalesubject's blood plasma or blood serum is less than 2.0, wherein thesubject is being considered for secondary prevention. In someembodiments, the present invention provides methods for treating afemale subject with an LDL-C/HDL-C ratio in a subject's blood plasma orblood serum of greater than 2.0. In some embodiment, the me method isfor secondary prevention. See Walldius, 2006.

The present invention provides methods for reducing in a subject's bloodplasma or blood serum an abnormally high concentration of non-HDL-C,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a composition of the invention.

In some embodiments, an “abnormally high concentration” of non-HDL-C ina subject's blood plasma or blood serum is greater than 190 mg/dL. Insome embodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of non-HDL-C in a subject's bloodplasma or blood serum is less than 190 mg/dL. In some embodiments, thesubject has 0-1 CHD risk factors. In some embodiments, the presentinvention provides methods for reducing a subject's non-HDL-Cconcentration in the subject's blood plasma or blood serum, wherein thenon-HDL-C concentration is greater than 190 mg/dL. In some embodiments,the subject has 0-1 CHD risk factors. See Walldius, 2006.

In some embodiments, an “abnormally high concentration” of non-HDL-C ina subject's blood plasma or blood serum is greater than 160 mg/dL. Insome embodiments, the subject has 2 or more CHD risk factors. In someembodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of non-HDL-C in a subject's bloodplasma or blood serum is less than 160 mg/dL. In some embodiment, thesubject has 2 or more CHD risk factors. In some embodiments, the presentinvention provides methods for reducing a subject's non-HDL-Cconcentration in the subject's blood plasma or blood serum, wherein thesubject's non-HDL-C concentration is greater than 160 mg/dL. In someembodiments, the subject has 2 or more CHD risk factors. See Walldius,2006.

In some embodiments, an “abnormally high concentration” of non-HDL-C ina subject's blood plasma or blood serum is greater than 130 mg/dL. Insome embodiments, the subject has a CHD or a CHD risk equivalent. Insome embodiments, the reducing is to a normal concentration. In someembodiments, the normal concentration of non-HDL-C in a subject's bloodplasma or blood serum is less than 130 mg/dL. In some embodiments, thesubject has a CHD or a CHD risk equivalent. In some embodiments, thepresent invention provides methods for reducing a subject's non-HDL-Cconcentration in the subject's blood plasma or blood serum, wherein thesubject's non-HDL-C concentration is greater than 130 mg/dL. In someembodiments, the subject has a CHD or a CHD risk equivalent. SeeWalldius, 2006.

The present invention provides methods for elevating in a subject'sblood plasma or blood serum an abnormally low concentration of ahigh-density lipoprotein (HDL)-associated protein, HDL-cholesterol(HDL-C), apolipoprotein A-I, or apolipoprotein E, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or a composition of the invention. In someembodiments, the HDL-associated protein is apolipoprotein A-I (apo A-I),apolipoprotein A-II (apo A-II), apolipoprotein A-IV (apo A-IV) orapolipoprotein E (apo E).

In some embodiments, an “abnormally low concentration” of HDL-C in asubject's blood plasma or blood serum is less than 40 mg/dL. In someembodiments, the elevating is to a normal concentration. In someembodiments, the normal concentration of HDL-C in a subject's bloodplasma or blood serum is greater than 40 mg/dL. In some embodiments, thepresent invention provides methods for elevating HDL-C concentration ina subject's blood plasma or blood serum, where the subject's HDL-Cconcentration is less than 40 mg/dL. In some embodiments, the subject isa male subject. In some embodiments, the subject is a female subject.

In some embodiments, an “abnormally low concentration” of HDL-C in amale subject's blood plasma or blood serum is less than 45 mg/dL. Insome embodiments, the normal concentration of HDL-C in a male subject'sblood plasma or blood serum is greater than 45 mg/dL. In someembodiments, the present invention provides methods for elevating HDL-Cconcentration in a male subject's blood plasma or blood serum, where thesubject's HDL-C concentration is less than 45 mg/dL.

In some embodiments, an “abnormally low concentration” of HDL-C in afemale subject's blood plasma or blood serum is less than 50 mg/dL. Insome embodiments, the normal concentration of HDL-C in a femalesubject's blood plasma or blood serum is greater than 50 mg/dL. In someembodiments, the normal concentration of HDL-C in a female subject'sblood plasma or blood serum is greater than 55 mg/dL. In someembodiments, the present invention provides methods for elevating HDL-Cconcentration in a female subject's blood plasma or blood serum, wherethe subject's HDL-C concentration is less than 50 mg/dL. In someembodiments, the present invention provides methods for elevating HDL-Cconcentration in a female subject's blood plasma or blood serum wherethe subject's HDL-C concentration is lower than 55 mg/dL.

In some embodiments, the present invention provides methods forelevating HDL-C concentration in a subject's blood plasma or blood serumto 45 mg/dL or greater, where the subject's HDL-C concentration in asubject's blood plasma or blood serum is less than 40 mg/dL. In someembodiments, the present invention provides methods for elevating HDL-Cconcentration in a subject's blood plasma or blood serum to 50 mg/dL orgreater, where the subject's HDL-C concentration in a subject's bloodplasma or blood serum is less than 40 mg/dL. In some embodiments, thepresent invention provides methods for elevating HDL-C concentration ina subject's blood plasma or blood serum to 55 mg/dL or greater, wherethe subject's HDL-C concentration in a subject's blood plasma or bloodserum is less than 40 mg/dL.

In some embodiments, the present invention provides methods forelevating HDL-C concentration in a male subject's blood plasma or bloodserum to 50 mg/dL or greater, where the subject's HDL-C concentration ina subject's blood plasma or blood serum is less than 45 mg/dL. In someembodiments, the present invention provides methods for elevating HDL-Cconcentration in a female subject's blood plasma or blood serum to 50mg/dL or greater, where the subject's HDL-C concentration in a subject'sblood plasma or blood serum is less than 50 mg/dL. In some embodiments,the present invention provides methods for elevating HDL-C concentrationin a female subject's blood plasma or blood serum to 55 mg/dL orgreater, where the subject's HDL-C concentration in a subject's bloodplasma or blood serum is less than 50 mg/dL.

The present invention provides methods for promoting clearance oftriglyceride from a subject's blood plasma or blood serum, comprisingadministering to a subject in need thereof an effective amount of thecompound of the invention or the composition of the invention.

The present invention provides methods for increasing an abnormally lowglucose metabolism or increasing an abnormally low lipid metabolism in asubject, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or a composition of theinvention. In some embodiments, the method for increasing an abnormallylow glucose metabolism increases insulin sensitivity or oxygenconsumption in a subject. In some embodiments, the method for increasingan abnormally low glucose metabolism reduces blood insulin, bloodglucose, or glycated hemoglobin in a subject's blood plasma or bloodserum. In some embodiments, the methods for increasing an abnormally lowlipid metabolism reduces a concentration of LDL or free triglyceride ina subject's blood plasma or blood serum, or inhibits saponified ornon-saponified fatty acid synthesis.

In some embodiments, a subject with abnormally low glucose metabolismhas an abnormally high concentration of glucose or hemoglobin (Hb) inthe subject's blood plasma or blood serum. In some embodiments, thepresent invention provides methods for reducing an abnormally highconcentration of glucose or hemoglobin in a subject's blood plasma orblood serum. In some embodiments, the method increases abnormally lowglucose metabolism. An “abnormally high concentration” of glucose in asubject's blood plasma or blood serum in a two-hour GTT is greater than7.8 mmol/L (140 mg/dL). In some embodiments, reducing is to a normalconcentration. In some embodiments, the normal concentration of glucosein a subject's blood plasma or blood serum in a two-hour GTT is lessthan 7.8 mmol/L (140 mg/dL). In some embodiments, the present inventionprovides methods for increasing abnormally low glucose metabolism in asubject's blood plasma or blood serum, where the subject's glucoseconcentration in the subject's blood plasma or blood serum in a two-hourGTT is greater than 7.8 mmol/L (140 mg/dL). In some embodiments, thepresent invention provides methods for increasing abnormally low glucosemetabolism in a subject, where the subject's glucose concentration inthe subject's blood plasma or blood serum in a two-hour GTT ranges from7.8 mmol/L (140 mg/dL) to 11.1 mmol/L (200 mg/dL). In some embodiments,the present invention provides methods for increasing abnormally lowglucose metabolism in a subject, where the subject's glucoseconcentration in the subject's blood plasma or blood serum in a two-hourGTT is above 11.1 mmol/L (200 mg/dL).

In some embodiments, the present invention provides methods forincreasing abnormally low glucose metabolism in a subject, where thesubject has impaired glucose tolerance. In some embodiments, the presentinvention provides methods for increasing abnormally low glucosemetabolism in a subject, where the subject has diabetes. In someembodiments, the present invention provides methods for increasingabnormally low glucose metabolism in a subject, where the subject hasgestational diabetes.

A low lipid metabolism can be characterized by dyslipidemia (using theLDL-C, TGs, non-HDL-chol, apo B, apo C-III or apo C-II values) but alsowith elevated concentration of transaminases. In some embodiments, thesubject having a low lipid metabolism also has dyslipidemia.

The present invention provides methods for treating or preventing asymptom of a disease selected from inflammation, systemic lupuserythematosus, lupus nephritis, or arthritis, comprising administeringto a subject in need thereof an effective amount of a compound of theinvention or a composition of the invention. In some embodiments, thearthritis is adjuvant arthritis or type II collagen-induced arthritis.In some embodiments, the symptom is nephritis, kidney failure, or kidneyfunction reduction. In some embodiments, the kidney function reductionrequires renal dialysis.

The present invention provides methods for reducing fat content of meatin livestock, comprising administering to livestock an effective amountof a compound of the invention or a composition of the invention.

The present invention provides methods for reducing cholesterol contentof a fowl egg, comprising administering to a fowl species an effectiveamount of a compound of the invention or a composition of the invention.

In some embodiments, the methods of the invention provide administeringa dosage form of the compounds of the invention or the compositions ofthe invention hourly, daily, weekly, or monthly. The dosage forms andformulations of the present invention may be administered three times aday, twice a day or once a day. The dosage forms of the presentinvention can be administered with food or without food. An appropriatelength of the treatment, dosages, and route of administration can bedetermined and/or adjusted by a physician.

In some embodiments of the methods of the invention, the subject is ahuman subject.

5.5. Synthesis of Compounds of the Invention

Compounds of the invention can be synthesized by conventional means.Exemplary processes for synthesizing exemplary compounds of Formula (A)and Formula (B) are described in Examples 1-3, infra. WO 2011/020001,the contents of which are incorporated herein by reference in theirentireties, describes PPAR modulator compounds (described therein ascompounds of Formulas (I)-(XX)) and processes for their synethesis.Compounds of Formulas (I)-(XX) described in WO 2011/020001 can be usedas starting materials for synthesis of compounds of Formulas (C)-(H) and(J)-(W) of the present invention, respectively. For example, compoundsof WO 2011/020001 having a ketone can be reduced with a reducing agent,such as NaBH₄, optionally in the presence of a Lewis acid, such asCeCl₃, or in an alcohol solvent, such as methanol, to provide convertthe ketone group to a hydroxyl group. Similarly, carboxylic acid groupsof compounds of WO 2011/020001 can be reduced to a hydroxymethyl groupusing a reducing reagent, such as LiAlH₄, followed by an aqueous acidworkup to provide a compound of the invention.

WO 2017/062468, the contents of which are incorporated herein byreference in their entireties, describe PPAR modulator compounds(described therein as compounds of Formulas (I)-(III)) and processes fortheir synthesis. Compounds of Formulas (I)-(III) described in WO2017/06246 can be used as starting materials for synthesis of compoundsof Formulas (X)-(Z) of the present invention, respectively. Carboxylicacid groups of compounds of WO 2017/06246 can be reduced to ahydroxymethyl group using a reducing reagent, such as LiAlH₄, followedby an aqueous acid workup to provide a compound of the invention.

WO 2017/180818, the contents of which are incorporated herein byreference in their entireties, describe PPAR modulator compounds(described therein as compounds of Formulas (I)) and processes for theirsynthesis. Compounds of Formula (I) described in WO 2017/180818 can beused as starting materials for synthesis of compounds of Formula (AA) ofthe present invention. Carboxylic acid groups of compounds of WO2017/180818 can be reduced to a hydroxymethyl group using a reducingreagent, such as LiAlH₄, followed by an aqueous acid workup to provide acompound of the invention.

WO 2018/067857, the contents of which are incorporated herein byreference in their entireties, describe PPAR modulator compounds(described therein as compounds A, B, and C) and processes for theirsynthesis. Compounds B and C described in WO 2018/067857 can be used asstarting materials for synthesis of Compounds VII and VIII. Carboxylicacid groups of compounds of WO 2017/180818 can be reduced to ahydroxymethyl group using a reducing reagent, such as LiAlH₄, followedby an aqueous acid workup to provide a compound of the invention.

6. EXAMPLES 6.1. Example 1. Synthesis of Compound I

(Z)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoicacid (“Compound A”) is synthesized according to US2006/0142611. CompoundA is then reduced using a reducing agent, such as NaBH₄, optionally inthe presence of a Lewis acid, such as CeCl₃, or in an alcohol solvent,such as methanol, to provide Compound I racemate. Compound I racemate isthen resolved to provide its (S)- and (R)-enantiomers, each beingsubstantially free of its corresponding opposite enantiomer, using achiral high performance liquid chromatography.

6.2. Example 2. Synthesis of Compound II

Acetal Compound B is synthesized from Compound A and ethylene glycol inthe presence of catalytic acid, such as 0.1 M HCl. See, e.g., Dong,J-L., et al. ACS Omega, 2018, 3, 4974 for acetal formation specificallyon □□□-unsaturated ketones. The carboxyl group of Compound B issubsequently reduced to a hydroxymethyl group using a reducing reagent,such as LiAlH₄, followed by an aqueous acid workup, which removes theacetal to provide Compound II.

6.3. Example 3. Synthesis of Compound III

Compound II is reduced using a reducing agent, such as NaBH₄, optionallyin the presence of a Lewis acid, such as CeCl₃, or in an alcoholsolvent, such as methanol, to provide Compound III racemate. CompoundIII racemate is then resolved to provide its (S)- and (R)-enantiomers,each being substantially free of its corresponding opposite enantiomer,using a chiral high performance liquid chromatography.

6.4. Example 4. Hepatic and Peripheral Insulin Sensitive Effects in RatsFed a High Fat/Medium Fructose Diet (Western Diet)

After 8 weeks of high fat diet, rats are treated for 5 weeks withpioglitazone (10 mg/kg), metformin (50 mg/kg), an illustrative compoundof the invention (3 and 10 mg/kg), alone or in association withmetformin (50 mg/kg), and GW501516(2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]aceticacid) (10 mg/kg; ligand/GSK). Body weight can be decreased by metforminand this effect can be emphasized when it is associated with theillustrative compound of the invention in a dose of 10 mg/kg. After 17days of treatment, rats are fasted for 4 hours and blood is sampled.

The glucose tolerance is assessed after 21 days of treatment by an oralglucose load performed after 6 hours of fasting.

After 5 weeks of treatment, an euglycemic-hyperinsulinemic clampprocedure is performed in awake rats. Two doses of insulin are infusedwith 3H-glucose: 0.2 U/kg/h to assess an effect on hepatic glucoseproduction (HGP) and 0.8 U/kg/h to inhibit HGP and then to assess aneffect on whole body glucose utilization.

6.4.1. Animal Model

Male Sprague Dawley (SD) rats (250-275 g) are first fed with the westerndiet during 8 weeks for inducing insulin resistance. The first set ofrats undergoes an oral glucose tolerance test (OGTT) after 3 weeks oftreatment (half rats/group of the clamp arm) and the second set alsoundergoes an OGTT after 3 weeks of treatment (half rats/group of clamparm) and the histology study (3 rats/group).

Rats of each set are screened and randomized into the several groupsaccording to their fasted (4 h) plasma glucose, insulin levels (forhomeostatic model assessment of insulin resistance (HOMA-IR)calculation) and body weight. Rats that do not respond to the westerndiet are excluded from the study.

Homogenous mild obese and insulin resistant rats are allocated into thedifferent treatment groups and western diet is continued until the endof the experiment. Given that, the 2 series started with a gap of oneweek.

6.4.2. Treatments

Dosage regimen: Rats are treated once daily via the oral route, in themorning. The duration of the treatment is between 5 and 5.5 weeks.

6.4.3. Test Groups

-   -   Group 1: vehicle (n=12)    -   Group 2: pioglitazone, 10 mg/kg (n=12)    -   Group 3: metformin, 50 mg/Kg (n=12)    -   Group 4: an illustrative compound of the invention, 3 mg/Kg        (n=12)    -   Group 5: an illustrative compound of the invention, 10 mg/Kg        (n=12)    -   Group 6: an illustrative compound of the invention, 3        mg/Kg+metformin 50 mg/kg (n=12)    -   Group 7: an illustrative compound of the invention, 10        mg/Kg+metformin 50 mg/kg (n=12)    -   Group 8: GW501216, 10 mg/Kg (n=12)

6.4.4. Fasting Conditions

Fasting conditions for the OGTT and the clamp procedure: food is removedfrom the cage and litter is changed just before lights-off (between 7:30and 8:00 am). Then each experiment starts after about 6 hours of fasting(between 1:30 and 2:00 pm).

Fasting conditions for plasma parameters: food is removed from the cageand litter is changed 4 hours after lights-off (between 11:30 am andnoon). Then blood collection starts after 4 hours of fasting (at 4:00pm).

6.4.5. Oral Glucose Tolerance Test

After 3 weeks of treatment, rats are fasted for 6 hours and an oralglucose load (2.5 g/kg body weight) is performed. Blood glucose ismeasured 30 minutes before glucose load and at 0, 15, 30, 60, 90 and 120minutes.

6.4.6. Euglycemic-Hyperinsulinemic 2 Steps Clamp with 3H-Glucose

After 4 weeks of treatment, a catheter is implanted into the femoralvein under isoflurane anesthesia and a period of 5-6 days is respectedfor recovery. Rats that do not recover body weight are excluded from thestudy. The accepted body weight loss estimated on the day of perfusionis fixed at 5% in groups where treatments should not affect body weight(as seen during body weight follow-up) (vehicle, pioglitazone and theillustrative compound of the invention, mg/kg groups) and at 10% wheretreatments decreases it (the 5 other groups). The morning of the clampprocedure, rats are treated and fasted for 6 hours prior to tracer,glucose and insulin infusions. The beginning of the clamp procedure isperformed in the middle of the dark cycle.

The euglycemic-hyperinsulinemic 2 steps insulin clamp is performed using0.2 U/kg/h and 0.8 U/kg/h insulin infusion associated with 3H-glucoseinfusion. Thereafter the following parameters are assessed:

-   -   Whole body glucose utilization    -   Hepatic glucose production    -   Glucose infusion rate    -   Whole body glycogen and glycolytic rates

6.4.7. In Vivo Glucose Utilization Rate

During the clamp procedure, a bolus (30 μCi) of D-[3-3H]glucose is firstinjected followed by 4 μCi/min/kg infusion rate during all theexperiment to ensure a detectable plasma D[3-3H]glucose enrichment. Abolus of insulin (100 mU) is first injected, and insulin is then infusedat a rate of 0.2 U/kg/h for the first 2 hours and 0.8 U/kg/h from 120minutes to 210 minutes.

Throughout the infusion, glycaemia is assessed with a blood glucosemeter from the tip of the tail vein when needed. Euglycemia ismaintained by periodically (every 10 minutes) adjusting a variableinfusion of 30% glucose. Plasma glucose concentrations andD-[3-3H]glucose specific activity are determined during stable phase in10 μl of blood sampled from the tip of the tail vein every 20 minutesfrom 60 to 120 minutes during the first step and from 150 to 210 minutesduring the second step.

For glucose turnover measurements, D-[3-3H]glucose enrichments aredetermined from total blood after deproteinization by a Zn(OH)₂precipitate. Briefly, an aliquot of the supernatant is evaporated todryness to determine the radioactivity corresponding to D-3-3H. In asecond aliquot of the same supernatant, glucose concentration isassessed by the glucose oxidase method (Biomérieux, France).

6.4.8. Calculation

Calculations for glucose turnover measurements are made from parametersobtained during the infusions in steady-state condition (60-120 and160-210 minutes). Briefly, the D-[3-3H]glucose specific activity iscalculated by dividing the D-[3-3H]glucose enrichment by the plasmaglucose concentration. The whole body glucose turnover rate iscalculated by dividing the rate of D[3-3H]glucose by the D-[3-3H]glucoseplasma specific activity. For each rat, the mean values are calculatedand averaged with values from rats of the same group. The whole bodyglycolysis rate are measured by assessing the amount of tritiated wateraccumulated in the blood during the 3H-glucose infusion and the wholebody glycogen synthesis rate are calculated by the difference betweenthe whole body glucose turnover and the whole body glycolysis rate.

6.4.9. Blood, Tissue Collection and Biochemistry

At the end of the clamp procedure (9.5 hours fasting), perirenal,retroperitoneal, epididymal and inguinal fat pads and liver weights arerecorded. Blood is collected from cardiac puncture and plasmas arestored at −80° C. for further assays if needed (depending on theradioactive state of samples). Liver triglyceride content is assessed(enzymatic-colorimetric method) as well as liver and adipose tissueTNF-α content (enzyme-linked immunosorbent assay (ELISA) method). See US2011/0092517, which is hereby incorporated by reference in its entirety.

6.5. Example 5. Mouse and Rat PPAR Transcriptional Activation inCell-Based Transactivation Assay

6.5.1. Assays with GAL4-PPAR Chimera Receptors

6.5.1.1. Receptor Expression Plasmids

An established chimeric receptor system (Lehmann J M et. al. J BiolChem. 1997; 272(6):3406-10) is utilized to allow comparison of therelative transcriptional activity of the receptor subtypes. Themammalian expression vectors pSG5-GAL4-PPARα, pSG5-GAL4-PPARγ andpSG5-GAL4-PPARδ from Homo sapiens (hs) (NM_006238, NM_015869,NM_001001928), Macaca mulatta (mm) (NM_001033029, XM_001116676,NM_001032860), Mus musculus (m) (NM_011144, U10375, NM_011146) andRattus norvegicus (r) (NM_013141, NM_013196, NM_013124), which expressthe ligand binding domains (LBDs) of human PPARα (amino acids 167-468for hs and m, amino acids 167-467 for mm), PPARγ1 (amino acids 176-477for hs, amino acids 204-505 for m and mm from PPARγ) and PPARδ (aminoacids 139-441 for hs and mm, amino acids 139-440 for m) each fused tothe yeast transcription factor GAL4 DNA binding domain (amino acid1-147) and the human glucocorticoid receptor (amino acids 1-76), arecloned.

Reporter plasmid: MH100×4-tk-luc (Forman B M et al. Cell. 199581(4):541-50) is used as the reporter plasmid.

6.5.1.2. Transient Transfection Assays

The African green monkey kidney cell line, CV-1 is used for thetransfection assays. CV-1 cells are seeded in 24-well plates at 0.5×10⁵cells per well and are cultured for 24 hours. Transfection mixtures forchimera receptors contain 30 ng of receptor expression plasmid, 120 ngof the reporter plasmid, 350 ng of pCMX-β-galactosidase (βGAL)expression plasmid as a control for transfection efficiency, 250 ng ofpGEM4 carrier plasmid and 2 μL of a lipofection reagent (Lipofectamine2000, Invitrogen). These mixtures are added to cells and incubated for 5hours according to the manufacturer's instructions. After thetransfection, cells are incubated for an additional 40 hours in thepresence of the illustrative compounds of the invention or eachreference compound at different concentrations. Cell lysates areprepared with a lysis buffer (Passive Lysis Buffer, Promega) and used inthe luciferase and βGAL assays. The luciferase and βGAL activity aremeasured with the Luciferase assay system (E4030, Promega) and with theβGAL enzyme assay system (E2000, Promega). Assays are performed intriplicate for GAL4-chimeras. Experiments are repeated at least threetimes.

6.5.1.3. Calculation of Relative PPAR Transactivation Activities

Each point of a relative PPAR transcriptional activity to maximalactivity is calculated based on the values bellow:

Luciferase activity of cells treated with a positive control (10⁻⁵ MGW-590735 for hPPARα, 3×10⁻⁵ M rosiglitazone maleate for hPPARγ assaysand 10⁻⁵ M GW-501516 for hPPARδ) as the maximal activity, and luciferaseactivity of cells treated with 0.1% of DMSO as the minimum activity.

6.5.1.4. Calculation of EC₅₀ Values

EC₅₀ values defined as the concentration of the illustrative compound ofthe invention and GW-501516 to produce 50% of maximal reporter activityre calculated with Prism software (Graphpad Software).

6.5.1.5. Experiments with 10% Serum vs 0.1% Serum.

Experiments at 2 serum concentrations: 10% and 0.1%. The EC50 arecalculated as previously described.

First, the assay is set up and the GAL4-chimeras/reporter plasmids arevalidated using homo-sapiens sequences of the different PPAR. Theexperiments are conducted at 10% and 0.1% serum with GW501516 (PPARδagonist).

Plasmid Reference is as indicated in US 2011/0092517, which is herebyincorporated by reference in its entirety.

7. SPECIFIC EMBODIMENTS

7.1. Specific Embodiments, Group 1

Various aspects of the present disclosure are described in the numberedembodiments set forth in the following numbered paragraphs, wherereference to a previous numbered embodiment refers to a previousnumbered embodiment in this Section 7.1.

1. A compound of Formula (A):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein:

each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, phenyl, or benzyl; or alternatively, R¹ and R² together withthe carbon atom to which R¹ and R² are attached form a C₃-C₇ cycloalkylgroup;

X is —CH₂OH, —COOH, —COH, —COOR³, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

2. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundis a racemate or a mixture of enantiomers or diastereomers.

3. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry and has the structure

4. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry and has the structure

5. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 3 or 4, wherein thecompound is substantially free of its corresponding oppositestereoisomer.

6. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 3-5, whereinthe compound has an olefin isomer configuration of (Z) or (E).

7. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundis a (Z)-isomer and has the structure

8. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundis a (E)-isomer and has the structure

9. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 7 or 8, wherein thecompound is substantially free of its corresponding other olefinconfiguration.

10. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 7-9, whereinthe compound has an hydroxyl-bearing allylic carbon atom having an (R)-or an (S)-stereochemistry.

11. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 1-10,wherein each R¹ and R² is independently —C₁-C₃ alkyl.

12. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 1-10,wherein each R¹ and R² is independently methyl.

13. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 1-12,wherein X is —CH₂OH, —COOH, —COH, —COOR³, or —COOCH₂CONR⁴R⁵.

14. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 1-12,wherein X is —CH₂OH or —COOH.

15. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 1-14,wherein n is 0 or 1.

16. A compound of Formula (B):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein:

-   -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹ and R²        together with the carbon atom to which R¹ and R² are attached        form a C₃-C₇ cycloalkyl group;    -   X is —CH₂OH, —COH, —COOCH₂CONR⁴R⁵, —SO₃H,

-   -   R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or        benzyl;    -   each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; or        alternatively, R⁴ and R⁵ together with the carbon atom to which        R⁴ and R⁵ are attached form a heterocycle;    -   each R⁶ and R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        or —C₂-C₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

17. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein the compoundis a mixture of (Z)- and (E)-isomers.

18. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 16, wherein the compoundis a (Z)-isomer and has the structure

19. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 16, wherein the compoundis a (E)-isomer and has the structure

20. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 18 or 19, wherein thecompound is substantially free of its corresponding other olefinconfiguration.

21. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 16-20,wherein each R¹ and R² is independently —C₁-C₃ alkyl.

22. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of embodiments 16-20, wherein each R¹ andR² is independently methyl.

23. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 16-22,wherein X is —CH₂OH, —COH, or —COOCH₂CONR⁴R⁵.

24. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 16-22,wherein X is —CH₂OH.

25. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of any one of the compound of embodiments 16-24,wherein n is 0 or 1.

26. A compound having the structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

27. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein the compoundis a racemate or a mixture of enantiomers.

28. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry and has the structure

29. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry and has the structure

30. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 28 or 29, wherein thecompound is substantially free of its corresponding opposite enantiomer.

31. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 28-30,wherein the compound has an olefin isomer configuration of (Z) or (E).

32. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein the compoundis a (Z)-isomer and has the structure

33. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein the compoundis a (E)-isomer and has the structure

34. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 32 or 33, wherein thecompound is substantially free of its corresponding other olefinconfiguration.

35. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 32-34,wherein the compound has an hydroxyl-bearing allylic carbon atom havingan (R)- or an (S)-stereochemistry.

36. A compound having the structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

37. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 36, wherein the compoundis a mixture of (Z)- and (E)-isomers.

38. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 36, wherein the compoundis a (Z)-isomer and has the structure

39. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 36, wherein the compoundis a (E)-isomer and has the structure

40. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 38 or 39, wherein thecompound is substantially free of its corresponding other olefinconfiguration.

41. A compound having the structure:

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

42. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein the compoundis a racemate or a mixture of enantiomers.

43. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(R)-stereochemistry and has the structure

44. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein the compoundhas an hydroxyl-bearing allylic carbon atom having an(S)-stereochemistry and has the structure

45. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 43 or 44, wherein thecompound is substantially free of its corresponding opposite enantiomer.

46. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 43-45,wherein the compound has an olefin isomer configuration of (Z) or (E).

47. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein the compoundis a (Z)-isomer and has the structure

48. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein the compoundis a (E)-isomer and has the structure

49. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 47 or 48, wherein thecompound is substantially free of its corresponding other olefinconfiguration.

50. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 47-49,wherein the compound has an hydroxyl-bearing allylic carbon atom havingan (R)- or an (S)-stereochemistry.

51. A composition comprising an effective amount of the compound orpharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of any one of embodiments 1-50 and a pharmaceuticallyacceptable carrier of vehicle.

52. The composition of embodiment 51, further comprising anothertherapeutically active agent.

53. The composition of embodiment 52, wherein the other therapeuticallyactive agent is a lipid lowering drug, statin, a cholesterol absorptioninhibitor, an antibody against PCSK9, an siRNA PCSK9, an anti-fibroticagent, a thyroid hormone, a selective thyroid receptor-βagonist,apoptosis signal-regulating kinase 1 (ASK1) inhibitor,acetyl-CoA carboxylase (ACC) inhibitor, an integrin antagonist, or anon-steroidal Farnesoid X receptor (FXR) agonist.

54. The composition of embodiment 53, wherein:

-   -   the lipid lowering drug is gemfibrozil, fenofibrate,        bezafibrate, clofibrate, ciprofibrate, clinofibrate, etofylline,        pirifibrate, simfibrate, tocofibrate, or pemafibrate;    -   the statin is atorvastatin, simvastatin, pravastatin,        rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin,        dalvastatin, dihydrocompactin, or cerivastatin, or a        pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof;    -   the cholesterol absorption inhibitor is ezetimibe;    -   the antibody against PCSK9 is evolocumab alirocumab,        bococizumab, 1D05-IgG2, RG7652, LY3015014, or LGT-209;    -   the siRNA PCSK9 is inclisiran;    -   the anti-fibrotic agent is nitazoxamide, tizoxanide, or        tizoxanide glucuronide, or a pharmaceutically acceptable salt,        solvate, ester, amide, or prodrug thereof;    -   the selective thyroid receptor-β agonist is VK2809, MGL-3196,        MGL-3745, SKL-14763, sobetirome, BCT304, ZYT1, MB-0781, or        eprotirome;        -   the ASK1 inhibitor is selonsertib;        -   the ACC inhibitor is firsocostat;        -   the integrin antagonist is an α5β1 inhibitor or a pan            integrin inhibitor; or        -   the FXR agonist is cilofexor.

55. A method for treating or preventing a liver disorder, dyslipidemia,dyslipoproteinemia, a renal disease, a disorder of glucose metabolism, adisorder of lipid metabolism, a disorder of glucid metabolism, acardiovascular disease, a vascular disease, a metabolic syndrome, acomplication associated with metabolic syndrome, a PPAR-associateddisorder, septicemia, a thrombotic disorder, obesity, diabeticnephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, acerebrovascular disease, a disorder related to neovascularization,hypertension, cancer, inflammation, an inflammatory disease, aneurodegenerative disease, an autoimmune disease, a neoplastic disease,muscle atrophy, cholestasis, mitochondrial dysfunction, an oculardisease, a lysosomal storage disease, a kidney disease, or impotence,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of any one of embodiments 1-50.

56. The method of embodiment 55, wherein the liver disorder involvespathological disruption, inflammation, degeneration, apoptosis, orproliferation of liver cells.

57. The method of embodiment 55, wherein the liver disorder is liverfibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD)or non-alcoholic steatohepatitis (NASH).

58. The method of embodiment 55, wherein the dyslipidemia ishyperlipidemia or an abnormally low concentration of high densitylipoprotein cholesterol (HDL-C) in the subject's blood plasma or bloodserum.

59. The method of embodiment 58, wherein the hyperlipidemia ishypercholesterolemia, familial hypercholesterolemia,hypertriglyceridemia, or familial combined hyperlipidemia.

60. The method of embodiment 58, wherein the hyperlipidemia ischaracterized by: an abnormally reduced or deficient lipoprotein lipaselevel or activity in the subject's blood plasma or blood serum, or anabnormally high concentration of ketone bodies, lipoprotein(a)cholesterol (Lp(a)-C), low density lipoprotein (LDL), very low densitylipoproteins cholesterol (VLDL-C) or non-esterified fatty acids in thesubject's blood plasma or blood serum.

61. The method of embodiment 60, wherein the reduced or deficientlipoprotein lipase level or activity is a result of a mutation in a geneencoding a lipoprotein lipase.

62. The method of embodiment 55, wherein the dyslipoproteinemia ischaracterized by an abnormally high concentration of LDL, apolipoprotein(a) or VLDL in a subject's blood plasma or blood serum, or an abnormallylow concentration of high density lipoprotein (HDL) or lipoproteinlipase in a subject's blood plasma or blood serum.

63. The method of embodiment 62, wherein the abnormally lowconcentration of the lipoprotein lipase is associated with: alipoprotein lipase mutation, hypoalphalipoproteinemia, a lipoproteinabnormality associated with diabetes, a lipoprotein abnormalityassociated with obesity, a lipoprotein abnormality associated withAlzheimer's disease, or familial combined hyperlipidemia.

64. The method of embodiment 55, wherein the renal disease is aglomerular disease, a tubular disease, a tubulointerstitial disease,acute or rapidly progressive renal failure, chronic renal failure,nephrolithiasis, or a tumor.

65. The method of embodiment 64 wherein:

-   -   the glomerular disease is an acute glomerulonephritis, a chronic        glomerulonephritis, a rapidly progressive glomerulonephritis, a        nephrotic syndrome, a focal proliferative glomerulonephritis, a        glomerular lesion associated with systemic disease, Goodpasture        syndrome, multiple myeloma, diabetes, neoplasia, sickle cell        disease or a chronic inflammatory disease;    -   the tubular disease is an acute tubular necrosis, an acute renal        failure, a polycystic renal disease, medullary sponge kidney, a        medullary cystic disease, nephrogenic diabetes, or a renal        tubular acidosis;    -   the tubulointerstitial disease is pyelonephritis, a drug- or        toxin-induced tubulointerstitial nephritis, a hypercalcemic        nephropathy, or a hypokalemic nephropathy; or    -   the tumor is renal cell carcinoma or nephroblastoma.

66. The method of embodiment 65, wherein the glomerular lesionassociated with systemic disease is systemic lupus erythematosus.

67. The method of embodiment 55, wherein the renal disease ishypertension, nephrosclerosis, microangiopathic hemolytic anemia,atheroembolic renal disease, diffuse cortical necrosis, or a renalinfarct.

68. The method of embodiment 67, wherein the hypertension is anessential hypertension, hyperpiesa, hyperpiersis, a malignanthypertension, a secondary hypertension, or a white-coat hypertension.

69. The method of embodiment 55, wherein the disorder of glucosemetabolism is an impaired glucose tolerance; an insulin resistance; aninsulin resistance-related breast, colon or prostate cancer; diabetes;pancreatitis; hypertension; polycystic ovarian disease; or an abnormallyhigh concentration of blood insulin or glucose in the subject's bloodplasma or blood serum.

70. The method of embodiment 69, wherein the diabetes is non-insulindependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus(IDDM), gestational diabetes mellitus (GDM), or maturity onset diabetesof the young (MODY).

71. The method of embodiment 55, wherein the vascular disease or thecardiovascular disease is a peripheral vascular disease, a coronaryheart disease, stroke, restenosis, arteriosclerosis, ischemia, anendothelium dysfunction, an ischemia-reperfusion injury, a myocardialinfarction, or a cerebral infarction.

72. The method of embodiment 55, wherein the PPAR-associated disorder isrheumatoid arthritis, multiple sclerosis, psoriasis, an inflammatorybowel disease, breast cancer, colon cancer, or prostate cancer.

73. The method of embodiment 55, wherein the PPAR-associated disorder isa vascular disease, a muscular disease, a demyelinating disease, amuscle structure disorder, a neuronal activation disorder, a musclefatigue disorder, a muscle mass disorder, a mitochondrial disease, amitochondrial dysfunction, a beta oxidation disease, or a metabolicdisease.

74. The method of embodiment 73, wherein:

-   -   the muscular disease is a muscular dystrophy disease;    -   the demyelinating disease is multiple sclerosis,        Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease,        encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy,        or Guillian-Barre syndrome;    -   the muscle structure disorder is Bethlem myopathy, central core        disease, congenital fiber type disproportion, distal muscular        dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD,        facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a        muscle sodium channel disorder, myotonic chondrodystrophy,        myotonic dystrophy, myotubular myopathy, nemaline body disease,        oculopharyngeal MD, or stress urinary incontinence;    -   the neuronal activation disorder is amyotrophic lateral        sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome,        Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, a        nerve lesion, peripheral neuropathy, spinal muscular atrophy,        tardy ulnar nerve palsy, or toxic myoneural disorder;    -   the muscle fatigue disorder is chronic fatigue syndrome,        diabetes (type I or II), a glycogen storage disease,        fibromyalgia, Friedreich's ataxia, intermittent claudication,        lipid storage myopathy, MELAS (mitochondrial encephalopathy,        lactic acidosis, and stroke-like episodes) syndrome,        mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy;    -   the muscle mass disorder is cachexia, cartilage degeneration,        cerebral palsy, compartment syndrome, critical illness myopathy,        inclusion body myositis, muscular atrophy (disuse), sarcopenia,        steroid myopathy, or systemic lupus erythematosus;    -   the mitochondrial disease is Alpers's disease, chronic        progressive external ophthalmoplegia (CPEO), Kearns-Sayra        syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS,        myoclonic epilepsy and ragged-red fiber disease (MERRF),        neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa,        Pearson syndrome, mitochondrial malfunction, or a mitochondrial        loss of functionality;    -   the beta oxidation disease is systemic carnitine transporter,        carnitine palmitoyltransferase (CPT) II deficiency, very        long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency,        trifunctional enzyme deficiency, medium-chain acyl-CoA        dehydrogenase (MCAD) deficiency, short-chain acyl-CoA        dehydrogenase (SCAD) deficiency, or riboflavin-responsive        disorders of p-oxidation (RR-MADD); or    -   the metabolic disease is hyperlipidemia, dyslipidemia,        hyperchlolesterolemia, hypertriglyceridemia, HDL        hypocholesterolemia, LDL hypercholesterolemia, HLD        non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia,        apolipoprotein A-1 hypoproteinemia, atherosclerosis, a disease        of arterial sclerosis, a disease of cardiovascular system,        cerebrovascular disease, peripheral circulatory disease,        metabolic syndrome, syndrome X, obesity, diabetes, type I        diabetes, type II diabetes, hyperglycemia, insulin resistance,        impaired glucose tolerance, hyperinsulinism, a diabetic        complication, cardiac insufficiency, cardiac infarction,        cardiomyopathy, hypertension, non-alcoholic fatty liver disease        (NAFLD), non-alcoholic steatohepatitis (NASH), a thrombus,        Alzheimer disease, a neurodegenerative disease, a demyelinating        disease, multiple sclerosis, adrenal leukodystrophy, dermatitis,        psoriasis, acne, skin aging, trichosis, inflammation, arthritis,        asthma, hypersensitive intestine syndrome, ulcerative colitis,        Crohn's disease, or pancreatitis.

75. The method of embodiment 74, wherein the muscular dystrophy diseaseis Duchenne muscular dystrophy, Becker muscular dystrophy, a limb-girdlemuscular dystrophy, congenital muscular dystrophy, facioscapulohumeralmuscular dystrophy, myotonic muscular dystrophy, oculopharyngealmuscular dystrophy, distal muscular dystrophy, or Emery-Dreifussmuscular dystrophy.

76. The method of embodiment 55, wherein the PPAR-associated disorder isan abnormally low concentration of HDL, an abnormally low concentrationof apolipoprotein A-I (apo A-I), an abnormally high concentration ofVLDL-C, an abnormally high concentration of low density lipoproteincholesterol (LDL-C), an abnormally high concentration of triglyceride,an abnormally high concentration of apolipoprotein B (apo B), anabnormally high concentration of apolipoprotein C-III (apo C-III) or anabnormally reduced ratio of post-heparin hepatic lipase to lipoproteinlipase activity in the subject's blood plasma or blood serum.

77. The method of embodiment 55, wherein the PPAR-associated disorder isan abnormally high concentration of HDL or an abnormally lowconcentration of apo A-I in the subject's lymph or cerebral fluid.

78. The method of embodiment 55, wherein the obesity is abdominalobesity.

79. The method of embodiment 55, wherein the cerebrovascular disease iscerebral ischemia.

80. The method of embodiment 55, wherein, the disorder related toneovascularization is retinopathy or diabetes.

81. The method of embodiment 55, wherein the cancer is a human sarcomaor human carcinoma.

82. The method of embodiment 55, wherein the cancer is fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,bone cancer, breast cancer, ovarian cancer, prostate cancer, esophagealcancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinoma,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acutelymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia,acute promyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocytic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, hairy cellleukemia, lymphoblastic leukemia, myelogenous leukemia,lymphocyticleukemia, myelocytic leukemia, polycythemia vera, multiplemyeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma,Waldenstrom's macroglobulinemia, or a heavy chain disease.

83. The method of embodiment 82, wherein the leukemia is acute orchronic lymphoblastic leukemia, myelogenous leukemia,lymphocyticleukemia, lymphocytic leukemia, or myelocytic leukemia.

84. The method of embodiment 83, wherein the myelocytic leukemia isacute and is myeloblastic, promyclocytic, myelomonocytic, monocytic orerythroleukemia.

85. The method of embodiment 83, wherein the lymphoma is Hodgkin'slymphoma or non-Hodgkin's lymphoma.

86. The method of embodiment 55, wherein the inflammatory disease ismultiple sclerosis, a chronic inflammatory disorder of a joint,arthritis, a respiratory distress syndrome, an inflammatory boweldisease, an inflammatory lung disorder, an inflammatory disorder, aninflammatory disorder of the gum, tuberculosis, leprosy, an inflammatorydisease of the kidney, an inflammatory disorder of the skin, aninflammatory disease of the central nervous system, a systemic lupuserythematosus (SLE) or an inflammatory disease of the heart.

87. The method of embodiment 86, wherein:

-   -   the arthritis is rheumatoid arthritis or osteoarthritis;    -   the inflammatory bowel disease is ileitis, ulcerative colitis or        Crohn's disease;    -   the inflammatory lung disorder is asthma or chronic obstructive        airway disease;    -   the inflammatory disorder of the eye is corneal dystrophy,        trachoma, onchocerciasis,    -   uveitis, sympathic ophthalmitis or endophthalmitis;    -   the inflammatory disorder of the gum is periodontitis or        gingivitis;    -   the inflammatory disease of the kidney is glomerulonephritis or        nephrosis;    -   the inflammatory disorder of the skin is acne, sclerodermatitis,        psoriasis, eczema, photoaging or wrinkles;    -   the inflammatory disease of the central nervous system is        AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's        disease, encephalomyelitis, or viral or autoimmune encephalitis;        or    -   the inflammatory disease of the heart is cardiomyopathy.

88. The method of embodiment 55, wherein the neurodegenerative diseaseis Alzheimer's disease or Huntington's disease.

89. The method of embodiment 55, wherein the autoimmune disease isimmune-complex vasculitis, systemic lupus or erythematodes.

90. The method of embodiment 55, wherein, the neoplastic disease iscarcinogenesis.

91. The method of embodiment 55, wherein the cholestasis is intrahepaticcholestatic disease or extrahepatic cholestatic disease.

92. The method of embodiment 91, wherein intrahepatic cholestaticdisease is primary biliary cholangitis (PBC), primary sclerosingcholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC),or Alagille syndrome (AS).

93. The method of embodiment 55, wherein the ocular disease is dry eye,meibomian gland dysfunction, a keratoconjunctiva epithelial disorder, acorneal epithelial disorder, or a corneal ulcer.

94. The method of embodiment 55, wherein the lysosomal storage disorderis neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington'sdisease, amyotrophic lateral sclerosis (ALS), Parkinson's disease,multiple system atrophy (MSA), progressive supranuclear palsy (PSP),corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), adisorder of the autophagy pathway, Tay-Sach's disease, Fabry disease,Niemann-Pick disease, Gaucher disease, Hunter syndrome,alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storagedisease, chronic hexosaminidase A deficiency, cystinosis, Danon disease,Farber disease, fucosidosis, galactosialidosis, or Batten disease.

95. The method of embodiment 55, wherein the kidney disease is renalischemia reperfusion injury.

96. The method of embodiment 55, wherein the impotence results fromdamages to a nerve, artery, a smooth muscle, or fibrous tissue;diabetes; kidney disease; alcoholism; multiple sclerosis;atherosclerosis; vascular disease; or neurologic disease.

97. A method for treating or preventing hyperlipemia, hyperlipidemia,hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, ordyslipidemia, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1-50.

98. The method of embodiment 97, wherein the hypercholesterolemia ishomozygous familial hypercholesterolemia.

99. A method for treating a subject having or preventing a subject fromhaving an abnormally high concentration in a subject's blood plasma orblood serum of high low-density lipoprotein (LDL), apolipoprotein B (apoB), lipoprotein(a) (Lp(a)), apolipoprotein (a), or very low-densitylipoprotein (VLDL), comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1-50.

100. A method for treating a subject having or preventing a subject fromhaving an abnormally low concentration in a subject's blood plasma orblood serum of high-density lipoprotein (HDL), comprising administeringto a subject in need thereof an effective amount of the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of any one of embodiments 1-50.

101. A method for treating a subject having or preventing a subject fromhaving an abnormally reduced or deficient lipoprotein lipaseconcentration or activity in a subject's blood plasma or blood serum,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of any one of embodiments 1-50.

102. The method of embodiment 101, wherein the reduced or deficientlipoprotein lipase level or activity is a result of a mutation in a geneencoding a lipoprotein lipase.

103. A method for treating or preventing hypoalphalipoproteinemia, alipoprotein abnormality associated with diabetes, a lipoproteinabnormality associated with obesity, a lipoprotein abnormalityassociated with Alzheimer's Disease, or familial combinedhyperlipidemia, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1-50.

104. A method for reducing in a subject's blood plasma or blood serum anabnormally high concentration of triglyceride, low-density lipoproteincholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C),non-high-density lipoprotein cholesterol, (non-HDL-C), lipoprotein(a)(Lp(a)), apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II orapolipoprotein C-III, comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1-50.

105. A method for elevating in a subject's blood plasma or blood seruman abnormally low concentration of a high-density lipoprotein(HDL)-associated protein, HDL-cholesterol, apolipoprotein A-1, orapolipoprotein E, comprising administering to a subject in need thereofan effective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1-50.

106. The method of embodiment 105, wherein the HDL-associated protein isapolipoprotein A-1 (apo A-I), apolipoprotein A-II (apo A-II),apolipoprotein A-IV (apo A-IV) or apolipoprotein E (apo E).

107. A method for promoting clearance of triglyceride from a subject'sblood plasma or blood serum, comprising administering to a subject inneed thereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1-50.

108. A method for increasing abnormally low glucose metabolism or lipidmetabolism in a subject, comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1-50.

109. The method of embodiment 108, wherein the method for increasingabnormally low glucose metabolism increases insulin sensitivity oroxygen consumption of a subject or decreases blood insulin, bloodglucose, or glycated hemoglobin in a subject's blood plasma or bloodserum.

110. The method of embodiment 108, wherein the method for increasingabnormally low lipid metabolism reduces a concentration of LDL or freetriglyceride in a subject's blood plasma or blood serum, or inhibitssaponified or non-saponified fatty acid synthesis.

111. A method for treating or preventing a symptom of a disease selectedfrom inflammation, systemic lupus erythematosus, lupus nephritis, orarthritis, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1-50.

112. The method of embodiment 111, wherein the arthritis is adjuvantarthritis or type II collagen-induced arthritis.

113. The method of embodiment 111, wherein the symptom is nephritis,kidney failure, or kidney function reduction.

114. A method for reducing the fat content of meat in livestock,comprising administering to livestock an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of any one of embodiments 1-50.

115. A method for reducing cholesterol content of a fowl egg, comprisingadministering to a fowl species an effective amount of the compound orthe pharmaceutically acceptable salt, solvate, ester, amide, or prodrugof the compound of any one of embodiments 1-50.

116. A method for treating a subject with acute kidney injury (AKI) orat risk for AKI, comprising administering to the subject an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of any one of embodiments 1 to50.

117. The method of embodiment 116, wherein the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound is administered intravenously, optionally wherein themethod comprises once daily intravenous administration, optionally forthree days.

118. The method of embodiment 116, wherein the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound is administered orally.

119. The method of any one of embodiments 116 to 118, wherein the AKI issepsis-related AKI.

120. The method of any one of embodiments 116 to 118, wherein the AKI isischemia/reperfusion AKI.

121. The method of any one of embodiments 116 to 118, wherein the AKI isfrom acute interstitial nephritis.

122. The method of any one of embodiments 116 to 118, wherein the AKI isfrom glomerular renal disease.

123. The method of any one of embodiments 116 to 118, wherein the AKI isfrom acute vasculitic renal disease.

124. The method of any one of embodiments 116 to 118, wherein the AKI isfrom ischemia.

125. The method of any one of embodiments 116 to 118, wherein the AKI isfrom toxic injury.

126. The method of any one of embodiments 116 to 118, wherein the AKI isfrom prerenal azotemia.

127. The method of any one of embodiments 116 to 118, wherein the AKI isfrom acute postrenal destructive nephropathy.

128. The method of any one of embodiments 116 to 118, wherein the AKI isfrom diabetes.

129. The method of any one of embodiments 116 to 118, wherein the AKI isfrom underlying renal insufficiency.

130. The method of any one of embodiments 116 to 118, wherein the AKI isfrom nephritic syndrome.

131. The method of any one of embodiments 116 to 118, wherein the AKI isfrom atherosclerotic disease.

132. The method of any one of embodiments 116 to 118, wherein the AKI isfrom hypotension.

133. The method of any one of embodiments 116 to 118, wherein the AKI isfrom hypoxia.

134. The method of any one of embodiments 116 to 118, wherein the AKI isfrom myoglobinuria-hematuria.

135. The method of any one of embodiments 116 to 118, wherein the AKI isfrom liver disease.

136. The method of any one of embodiments 116 to 118, wherein the AKI issecondary to a viral infection, optionally wherein the viral infectionis COVID-19.

137. The method of embodiment 136, wherein the subject has a viralinfection, optionally wherein the viral infection is COVID-19.

138. The method of 116 to 119, wherein the subject has sepsis.

139. The method of embodiment 137, wherein the sepsis is associated witha gram-negative bacterial infection.

140. The method of embodiment 138 or embodiment 139, wherein the subjecthas an intra-abdominal cavity infection.

141. The method of embodiment 138 or embodiment 139, wherein the subjecthas urosepsis.

142. The method of any one of embodiments 116 to 141, wherein thesubject is elderly.

143. The method of any one of embodiments 116 to 142, wherein thesubject is a surgical patient.

144. The method of embodiment 143, wherein the surgical patient has hada cardiovascular surgery, optionally which is a coronary artery bypassgraft (CABG) surgery and/or heart valve surgery.

145. The method of any one of embodiments 116 to 141, wherein thesubject is pregnant.

146. The method of any one of embodiments 116 to 145, wherein thesubject has been exposed to a nephrotoxic agent.

147. The method of embodiment 146, wherein the nephrotoxic agentcomprises cisplatin, gentamicin, cephaloridine, cyclosporine,amphotericin, carbon tetrachloride, trichloroethylene,dichloroacetylene, or a combination thereof.

148. The method of any one of embodiments 116 to 147, wherein thesubject has AKI.

149. The method of embodiment 148, wherein the effective amount iseffective to reduce the severity of the AKI.

150. The method of any one of embodiments 116 to 147, wherein thesubject is at risk for AKI.

151. The method of any one of embodiments 116 to 147, wherein thesubject is at risk for AKI following a cardiovascular surgery,optionally which is a coronary artery bypass graft (CABG) surgery and/orheart valve surgery.

152. The method of embodiment 150 or embodiment 151, wherein theeffective amount is effective to reduce the likelihood that the subjectwill develop AKI.

153. The method of any one of embodiments 150 to 152, wherein theeffective amount is effective to delay the onset of AKI.

154. The method of any one of embodiments 150 to 152, wherein theeffective amount is effective to prevent AKI.

155. The method of any one of embodiments 150 to 152, wherein if thesubject develops AKI, the effective amount is effective to reduce theseverity of the AKI.

156. The method of any one of embodiments 116 to 155, wherein thesubject has a SOFA score of 1 to 4 prior to administration of thecompound or the pharmaceutically acceptable salt, solvate, ester, amideor prodrug of the compound or the pharmaceutical composition.

157. The method of embodiment 156, wherein the subject has a SOFA scoreof 2 to 4 prior to administration.

158. The method of embodiment 156, wherein the subject has a SOFA scoreof 1 prior to administration.

159. The method of embodiment 156, wherein the subject has a SOFA scoreof 2 prior to administration.

160. The method of embodiment 156, wherein the subject has a SOFA scoreof 3 prior to administration.

161. The method of embodiment 156, wherein the subject has a SOFA scoreof 4 prior to administration.

162. The method of any one of embodiments 116 to 161, wherein thesubject has an endotoxin activity level of >0.6 prior to administration.

163. The method of any one of embodiments 116 to 162, wherein theeffective amount is effective to reduce the subject's endotoxin activitylevel.

7.2. Specific Embodiments, Group 2

Various aspects of the present disclosure are described in the numberedembodiments set forth in the following numbered paragraphs, wherereference to a previous numbered embodiment refers to a previousnumbered embodiment in this Section 7.2.

1. A compound of Formula (C):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or        benzothienyl, any of which is unsubstituted or substituted with        C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈        alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl,        nitro, amino, phenyl or pyridyl;    -   R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with a 3-7        membered cycloalkyl, or C₁₋₆ alkyl substituted with phenyl,        naphthyl or pyridyl, any of which is unsubstituted or        substituted with C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈        haloalkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl,        benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;    -   A is oxygen, sulfur or NR⁹ in which R⁹ is hydrogen or C₁₋₈        alkyl;    -   X is a C₁₋₈ alkylene chain which is unsubstituted or substituted        with C₁₋₈ alkyl, C₁₋₈ alkoxy or hydroxyl, and which has 0 or 1        double bonds;    -   Y is C(═O), C(═N—OR¹⁰), CH(OR¹¹), CH═CH, C≡C, or C(═CH₂) in        which each of R¹⁰ and R¹¹ is hydrogen or C₁₋₈ alkyl;    -   each of R³, R⁴ and R⁵ is independently hydrogen, C₁₋₈ alkyl,        C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈ alkenyl, C₂₋₈        alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro, amino,        phenyl, or pyridyl; optionally wherein at least one of R³, R⁴,        and R⁵ is not hydrogen;    -   B is CH or nitrogen;    -   Z is oxygen or sulfur;    -   each of R⁶ and R⁷ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈        haloalkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

2. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein R¹ is phenylwhich can have substituents selected from the group consisting of C₁₋₈alkyl, C₁₋₈ alkyl having 1-3 halogen atoms, C₁₋₈ alkoxy, C₁₋₈ alkoxyhaving 1-3 halogen atoms, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl.

3. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1 or embodiment 2,wherein R² is C₂₋₈ alkyl.

4. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 3,wherein R¹ is attached to the 2nd position, and (i) R⁴ is attached tothe 4th position and —X—Y— is attached to the 5th position, or (ii) R⁴is attached to the 5th position and —X—Y— is attached to the 4thposition.

5. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 4,wherein A is oxygen or sulfur.

6. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 5,wherein X is a C₁₋₈ alkylene chain.

7. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 6,wherein Y is C(═O).

8. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 7,wherein each of R³, R⁴, and R⁵ is hydrogen, C₁₋₈ alkyl or C₁₋₈ alkylhaving halogen.

9. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 8,wherein B is CH.

10. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 9,wherein Z is oxygen.

11. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 10,wherein each of R⁶ and R⁷ is hydrogen or C₁₋₄ alkyl.

12. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein:

-   -   R¹ is phenyl or naphthyl, each of which can have one or more        substituents selected from the group consisting of C₁₋₈ alkyl,        C₁₋₈ alkyl having halogen, C₁₋₈ alkoxy, C₁₋₈ alkoxy having        halogen, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl,        benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;    -   R² is C₂₋₃ alkyl;    -   A is oxygen or sulfur;    -   X is a C₁₋₈ alkylene chain which can have a C₁₋₈ alkyl        substituent and which can contain a double bond;    -   Y is C(═O), CH═CH, or C(═CH₂);    -   each of R³, R⁴ and R⁵ is hydrogen, C₁₋₈ alkyl, C₁₋₈ alkyl having        halogen, C₁₋₈ alkoxy, C₁₋₈ alkoxy having halogen, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro,        amino, phenyl, or pyridyl;    -   B is CH;    -   Z is oxygen or sulfur; and    -   each of R⁶ and R⁷ is hydrogen or C₁₋₈ alkyl

13. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 12, wherein X is a C₁₋₈alkylene chain.

14. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 12, wherein R¹ isattached to the 2nd position.

15. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 12 to 14,wherein R³, R⁴ and R⁵ other than hydrogens are placed at ortho-positionswith respect to Z.

16. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, wherein R¹ is phenylsubstituted with CF₃.

17. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1 or embodiment 16,wherein R² is isopropyl.

18. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to17, wherein A is sulfur.

19. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to18, wherein X is CH₂CH₂.

20. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to19, wherein Y is C(═O).

21. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to19, wherein Y is CH(OH).

22. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to21, wherein R³ is CH₃ and R⁴ and R⁵ are each hydrogen.

23. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to22, wherein B is CH.

24. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to23, wherein Z is oxygen.

25. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 and 16 to24, wherein R⁶ and R⁷ are each hydrogen.

26. A compound of Formula (D):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹ and R² independently is a hydrogen, a halogen, nitro,        C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₃ haloalkyl having 1 to 3 halogens,        C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈ alkenyl, C₂₋₈        alkynyl, 3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with        3-7 membered cycloalkyl, C₆₋₁₀ aryl which is optionally        substituted, arylalkyl group which has a C₆₋₁₀ aryl moiety and        C₁₋₈ alkyl moiety, a heterocyclic group or a heterocyclic-alkyl        group having a C₁₋₈ alkyl group;    -   each occurrence of R³, R⁴, and R⁵ is independently a hydrogen or        C₁₋₈ alkyl;    -   A is an oxygen atom, a sulfur atom, or NR³;    -   each of X¹, X², and Z independently is C(═O), C(═O)NH,        C(═N—OR⁴), CH(OR⁵), NH(C═O), NHSO₂, SO₂NH, CH═CH, C≡C, or a        bond; and    -   Y is C₁₋₈ alkylene;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

27. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26, wherein X¹ is C(═O),CH(OH), or a bond.

28. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 26 or embodiment 27,wherein X² is C(═O), CH(OH), or a bond.

29. A compound of Formula (E):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹¹ and R¹² independently is hydrogen, halogen, nitro,        hydroxyl, amino, C₁₋₈ alkyl, an C₁₋₈ alkoxy, C₁₋₈ haloalkyl        group having 1 to 3 halogens, C₁₋₈ haloalkoxy group having 1 to        3 halogens, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a 3-7 membered        cycloalkyl, C₁₋₈ alkyl having a 3-7 membered cycloalkyl        substituent, or phenyl, naphthyl, benzyl, phenethyl, pyridyl,        thienyl, furyl, quinolyl, or benzothienyl group which optionally        has a substituent which is a halogen atom, nitro, hydroxyl,        amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1 to 3        halogens, C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, 3-7 membered cycloalkyl group, C₁₋₈ alkyl group        having a 3-7 membered cycloalkyl substituent, phenyl or pyridyl;    -   each of X¹ and Z¹ independently is C(═O), C(═O)NH, C(═N—OR¹⁴),        CH(OR¹⁵), NH(C═O), NHSO₂, SO₂NH, CH═CH, C≡C, or a bond, wherein        each of R¹⁴ and R¹⁵ is a hydrogen or C₁₋₈ alkyl;    -   Y¹ is C₁₋₈ alkylene;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

30. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 29, wherein X¹ is C(═O),CH(OH), or a bond.

31. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 29 or embodiment 30,wherein Z¹ is C(═O), CH(OH), or a bond.

32. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 29 to 31,wherein X¹—Y¹—Z¹ is bonded to the 3 or 4 position of the phenyl ring.

33. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 29 to 32,wherein X¹ is a bond and Z¹ is (C═O).

34. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 29 to 33,wherein X¹—Y¹—Z¹ is bonded to the 4 position of the five membered ring.

35. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 29 to 34,wherein R¹¹ is a phenyl or naphthyl group which optionally has asubstituent selected from the group consisting chlorine, fluorine,hydroxyl, an alkyl group having 1-5 carbon atoms, and an alkyl grouphaving 1-5 carbon atoms, and it is bonded to the 2-position of the fivemembered ring.

36. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 29 to 35,wherein R¹² is an alkyl group having 3-6 carbon atoms, which is bondedto the 5-position of the 5 membered ring.

37. A compound of Formula (F):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A is O, S or NR⁷ in which R⁷ is hydrogen or C₁₋₈ alkyl;    -   B¹ is CW or N in which W is hydrogen or a bond; B² is O, S or        NR³ in which R^(a) is hydrogen or C₁₋₃ alkyl;    -   each of X¹ and X² is O, S, NH, NHC(═O), C(═O), C(═N—OR⁹),        CH(OR¹⁰), C═C, C≡C or a bond, wherein each of R⁹ and R¹⁰ is        hydrogen or C₁₋₈ alkyl;    -   Y is C₁₋₈ alkylene, which is unsubstituted or substituted with        C₁₋₈ alkyl or C₁₋₈ haloalkyl having 1-3 halogens;    -   Z is NH, O or S;    -   R¹ is aryl, which is unsubstituted or substituted with C₁₋₈        alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1-3 halogens,        hydroxyl, nitro, amino, phenyl, pyridyl or halogen, or a        heterocyclic group having a five to eight membered ring        comprising one to three hetero atoms each of which is        independently nitrogen, oxygen or sulfur and the other atoms are        carbon, optionally wherein a benzene ring is condensed with the        heterocyclic ring;    -   R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl having with 1-3 halogens, C₃₋₇        cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkyl substituted        with aryl, which is unsubstituted or substituted with C₁₋₈        alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1-3 halogens,        hydroxyl, nitro, amino, phenyl, pyridyl or halogen, or C₁₋₄        alkyl substituted with a heterocyclic group having five to eight        membered ring having one to three heteroatoms each of which is        independently nitrogen, oxygen or sulfur;    -   R³ is halogen, trifluoromethyl, C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈        alkynyl;    -   each of R⁴ and R⁵ is hydrogen, C₁₋₈ alkyl or C₁₋₈ haloalkyl        having 1-3 halogens;    -   each of Z and R³ is attached to the benzene ring, and X² is not        attached to the benzene ring;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

38. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 37, wherein X¹ is C(═O),CH(OH), or a bond.

39. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 37 or embodiment 38,wherein X² is C(═O), CH(OH), or a bond.

40. A compound of Formula (G):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹ and R⁴, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R² is hydrogen;    -   R³ is C₁₋₈ alkyl, or R³ is combined with R² to form ═O or        ═C(R⁷)(R⁸) in which each of R⁷ and R⁸ which are the same or        different, is a hydrogen or C₁₋₈ alkyl;    -   each of R⁵ and R⁶, which are the same or different, is a        hydrogen atom, C₁₋₈ alkyl, C₁₋₈ haloalkyl;    -   X and Y are the same or different and each represents CH or N;    -   Z is oxygen or sulfur;    -   A is a 5-membered heterocyclic group which is pyrazole,        thiophene, furan or pyrrole, wherein the heterocyclic group is        unsubstituted or substituted with C₁₋₈ alkyl having a        substituent which is C₁₋₈ alkyl, 3- to 7-membered cycloalkyl,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl group        substituted with a 3- to 7-membered cycloalkyl group, C₁₋₈        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, 5- or 6-membered        heterocyclic group, an aralkyl group having a C₆₋₁₀ aryl moiety        and a C₁₋₈ alkylene moiety, or 5- or 6-membered heterocyclic        group;    -   B is a C₁₋₈ alkylene chain which is unsubstituted or substituted        with C₁₋₈ alkyl, 3- to 7-membered cycloalkyl group, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl or        C₁₋₈ haloalkoxy, the alkylene group optionally having a double        bond in the case that the alkylene group has 2 to 6 carbon        atoms;    -   q is 0, 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

41. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 40, wherein A ispyrazole.

42. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, in which —(CH₂)_(q)—is attached the pyrazole at 1-position thereof

43. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 41, wherein —(CH₂)_(q)—is attached to the pyrazole at 3-position thereof.

44. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 42 or 43, in which —B—is attached to the pyrazole at 4- or 5-position thereof.

45. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 40, wherein A isthiophene, furan or pyrrole.

46. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 45, wherein —(CH₂)_(q)—is attached the 5-membered heterocyclic group at 2-position thereof

47. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 40, wherein A isthiophene.

48. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 47, in which —(CH₂)_(q)—is attached the thiophene at 2-position thereof.

49. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 48,wherein q is 0.

50. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 49,wherein each of X and Y is CH.

51. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 50, inwhich R² is combined with R³ to represent ═O.

52. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 51,wherein B represents an alkylene chain having 2 to 4 carbon atoms whichoptionally has a substituent selected from the group consisting of analkyl group having 1 to 8 carbon atoms and an alkyl group having 1 to 8carbon atoms and a halogen atom substituent.

53. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 52,wherein B is an ethylene chain.

54. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 53, inwhich R¹ and R⁴ are the same or different and each represents a hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbonatoms and a halogen atom substituent, or an alkoxy group having 1 to 8carbon atoms and a halogen atom substituent.

55. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 54, inwhich R⁵ and R⁶ are the same or different and each represents a hydrogenatom or an alkyl group having 1 to 8 carbon atoms

56. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 40 to 55, inwhich the substituent optionally attached to the heterocyclic group forA is an alkyl group having 1 to 8 carbon atoms or an alkyl group having1 to 8 carbon atoms and a halogen atom substituent.

57. A compound of Formula (H):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R¹¹ and R¹³, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R¹² is hydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to        7-membered cycloalkyl group substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered heterocyclic group,        an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene        moiety, or a C₁₋₈ alkyl group having a 5- or 6-membered        heterocyclic substituent;    -   R¹⁴ and R¹⁵ are the same or different and each is a hydrogen        atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl;    -   X¹ is CH or N;    -   Z¹ is oxygen or sulfur;    -   W¹ is oxygen or CH₂ when bond a is present and OH when bond a is        absent;    -   q is 2, 3, or 4.    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

58. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 57, wherein X¹ is CH.

59. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 57 or 58, whereinR¹¹-phenyl or R¹¹-pyridyl is attached to the pyrazole at 1-position.

60. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 57 or 58, whereinR¹¹-phenyl or R¹¹-pyridyl attached to the pyrazole at 3-position.

61. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 60, inwhich —(CH₂)_(q)— is attached to the pyrazole at 4- or 5-position.

62. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 61, inwhich R¹¹ and R¹³ are the same or different and each represents ahydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxygroup having 1 to 8 carbon atoms, a halogen atom, an alkyl group having1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy grouphaving 1 to 8 carbon atoms and a halogen atom substituent.

63. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 61, inwhich R¹¹ and R¹³ are the same or different and each represents an alkylgroup having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbonatoms and a halogen atom substituent.

64. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 63, inwhich R¹⁴ and R¹⁵ are the same or different and each represents ahydrogen atom or an alkyl group having 1 to 8 carbon atoms.

65. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 64, inwhich R¹² represents a hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxygroup having 1 to 8 carbon atoms and a halogen atom substituent.

66. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 64, inwhich R¹² represents an alkyl group having 1 to 8 carbon atoms, or analkyl group having 1 to 8 carbon atoms and a halogen atom substituent.

67. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 66, inwhich q is 2.

68. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 67,wherein bond a is absent and W¹ is OH.

69. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 57 to 67,wherein bond a is present and W¹ is oxygen.

70. A compound of Formula (J):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of R²¹ and R²³, which are the same or different, is a        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈        acyl group, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic        group;    -   R²² is hydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to        7-membered cycloalkyl group substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered heterocyclic group,        an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene        moiety, or a C₁₋₈ alkyl group having a 5- or 6-membered        heterocyclic substituent;    -   R²⁴ and R²⁵ are the same or different and each is a hydrogen        atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl;    -   X² is CH or N;    -   Z² is oxygen or sulfur;    -   W² is oxygen or CH₂ when bond a is present and OH when bond a is        absent;    -   r is 2, 3, or 4.    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

71. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 70, in which X² is CH.

72. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 70 or 71, in whichR²¹-phenyl or R²¹-pyridyl is attached to the thiophene at 2-position.

73. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 72, inwhich R²¹ and R²³ are the same or different and each represents ahydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxygroup having 1 to 8 carbon atoms, a halogen atom, an alkyl group having1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy grouphaving 1 to 8 carbon atoms and a halogen atom substituent.

74. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 72, inwhich R²¹ and R²³ are the same or different and each represents an alkylgroup having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbonatoms and a halogen atom substituent.

75. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 74, inwhich R²⁴ and R²⁵ are the same or different and each represents ahydrogen atom or an alkyl group having 1 to 8 carbon atoms.

76. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 75, inwhich R²² represents a hydrogen atom, an alkyl group having 1 to 8carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl grouphaving 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxygroup having 1 to 8 carbon atoms and a halogen atom substituent.

77. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 75, inwhich R²² represents an alkyl group having 1 to 8 carbon atoms, or analkyl group having 1 to 8 carbon atoms and a halogen atom substituent.

78. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 77, inwhich r is 2.

79. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 78,wherein bond a is absent and W² is OH.

80. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 70 to 78,wherein bond a is present and W² is oxygen.

81. A compound of Formula (K):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A is CH or nitrogen;    -   B, when bond a is present, is oxygen or C(R⁸)(R⁹) in which each        of R⁸ and R⁹ is independently hydrogen or C₁₋₈ alkyl; B, when        bond a is absent, is OH;    -   W¹ is a bond, C(═O), or (C(R^(1′))(R¹¹))_(m) in which each of        R¹⁰ and R¹¹ is independently a hydrogen or C₁₋₈ alkyl group and        m is 1, 2, or 3;    -   X and Y differ from each other, and each is an oxygen atom, a        sulfur atom, a nitrogen atom, or CR¹² in which R¹² is a hydrogen        or C₁₋₈ alkyl;    -   Z¹ is a bond, oxygen, sulfur, or C(R¹³)(R¹⁴) in which each of        R¹³ and R¹⁴ is independently a hydrogen or C₁₋₈ alkyl;    -   each of R¹, R², and R³, is independently a hydrogen, C₁₋₈ alkyl,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈        haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acyl group,        C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group;    -   each of R⁴ and R⁵ is independently hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl;    -   each of R⁶ and R⁷ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, or C₁₋₈ haloalkyl    -   r is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

82. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 81, wherein A is CH.

83. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 81 or 82, in which W¹ isa bond.

84. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 81 or 82, in which W¹ ismethylene or C(═O).

85. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 84, inwhich X and Y are different from each other and each is an oxygen atom,a sulfur atom or a nitrogen atom.

86. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 85, X is a sulfur atomand Y is a nitrogen atom.

87. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 86, inwhich Z¹ is an oxygen atom or a sulfur atom.

88. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 87, inwhich R¹, R² and R³ independently is a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkylgroup having 1 to 8 carbon atoms which is substituted with a halogenatom, or an alkoxy group having 1 to 8 carbon atoms which is substitutedwith a halogen atom.

89. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 88, inwhich each of R⁴ and R⁵ independently is a hydrogen atom or methyl.

90. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 89, inwhich each of R⁶ and R⁷ independently is a hydrogen atom or an alkylgroup having 1 to 8 carbon atoms

91. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 90, inwhich n is an integer of 2 to 4.

92. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 91, in which n is 2.

93. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 92,wherein bond a is absent and B is OH.

94. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 81 to 92,wherein bond a is present and B is oxygen.

95. A compound of Formula (L):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   B, when bond a is present, is oxygen; B, when bond a is absent,        is OH;    -   W² is a bond, C(═O), or CH₂;    -   Z² is oxygen or sulfur;    -   each of R²¹, R²², and R²³ is independently a hydrogen, C₁₋₈        alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈        haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acyl group,        C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group;    -   each of R²⁴ and R²⁵ is independently hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

96. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 95, in which W² is abond.

97. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 95 or 96, inwhich R²¹, R²² and R²³ independently is a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkylgroup having 1 to 8 carbon atoms which is substituted with a halogenatom, or an alkoxy group having 1 to 8 carbon atoms which is substitutedwith a halogen atom.

98. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 95 to 97, inwhich each of R²⁴ and R²⁵ independently is a hydrogen atom or methyl.

99. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 95 to 98,wherein bond a is absent and B is OH.

100. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 95 to 98,wherein bond a is present and B is oxygen.

101. A compound of Formula (M):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of W¹ and W² is independently nitrogen or CH;    -   X is nitrogen or CH;    -   Y is oxygen or sulfur;    -   Z is a bond, oxygen, sulfur or NR⁵, in which R⁵ is hydrogen or        C₁₋₈ alkyl;    -   each of R¹ and R² is independently hydrogen, halogen, hydroxyl,        nitro, amino, C₁₋₈ alkyl, 3- to 7-membered cycloalkyl group,        C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3-        to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, C₆₋₁₀ aryl, 5- or 6-membered heterocyclic group, an        aralkyl group having C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene, or        C₁₋₈ alkyl having a 5- or 6-membered heterocyclic substituent;    -   each of R³ and R⁴ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈        haloalkyl;    -   A is a 5-membered heterocycle which is pyrazole, thiophene,        furan, isoxazole, isothiazole or pyrrole, in which the        5-membered heterocycle is unsubstituted or substituted with        halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl, 3- to 7-membered        cycloalkyl group, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈        alkyl having a 3- to 7-membered cycloalkyl substituent, C₁₋₃        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5- or 6-membered        heterocyclic group, an aralkyl group having a C₆₋₁₀ aryl moiety        and C₁₋₈ alkylene moiety, or C₁₋₈ alkyl group having a 5- or        6-membered heterocyclic substituent;    -   B is a bond or C₁₋₈ alkylene which is unsubstituted or        substituted with C₁₋₃ alkyl, 3- to 7-membered cycloalkyl, C₁₋₃        alkoxy or a halogen substituent, optionally wherein the C₁₋₃        alkylene has a double or triple bond;    -   r is 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

102. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 101, in which each of W¹and W² represents CH.

103. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 101, in which W¹represents CH and W² represents a nitrogen atom

104. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 103,in which X represents a nitrogen atom.

105. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 103,in which X represents a nitrogen atom and Y represents an oxygen atom.

106. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 103,in which X represents CH and Y represents an oxygen atom.

107. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 106,in which Z represents an oxygen atom or a sulfur atom.

108. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 107,in which each of R¹ and R² independently represents a hydrogen atom, ahalogen atom, a hydroxyl group, a nitro group, an amino group, an alkylgroup having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbonatoms, an alkyl group having 1 to 8 carbon atoms and a halogensubstituent, or an alkoxy group having 1 to 8 carbon atoms and a halogensubstituent.

109. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 108,in which each of R³ and R⁴ independently represents a hydrogen atom oran alkyl group having 1 to 8 carbon atoms.

110. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 109,in which A represents pyrazole, thiophene or furan which may have asubstituent selected from the group consisting of a halogen atom, ahydroxyl group, a nitro group, an amino group, an alkyl group having 1to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl grouphaving 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms,an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and a 3- to 7-membered cycloalkyl substituent, an alkylgroup having 1 to 8 carbon atoms and a halogen substituent, an alkoxygroup having 1 to 8 carbon atoms and a halogen substituent, an arylgroup having 6 to 10 carbon atoms, a 5- or 6-membered heterocyclicgroup, an aralkyl group having an aryl moiety of 6 to 10 carbon atomsand an alkylene moiety of 1 to 8 carbon atoms, and an alkyl group having1 to 8 carbon atoms and a 5- or 6-membered heterocyclic substituent.

111. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 109,in which A represents pyrazole, thiophene or furan which may have asubstituent selected from the group consisting of a halogen atom, ahydroxyl group, a nitro group, an amino group, an alkyl group having 1to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkylgroup having 1 to 8 carbon atoms and a halogen substituent, or an alkoxygroup having 1 to 8 carbon atoms and a halogen substituent.

112. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 109,in which A represents pyrazole which may have a substituent selectedfrom the group consisting of a halogen atom, a hydroxyl group, a nitrogroup, an amino group, an alkyl group having 1 to 8 carbon atoms, analkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8carbon atoms and a halogen substituent, and an alkoxy group having 1 to8 carbon atoms and a halogen substituent.

113. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 112,in which B represents an alkylene chain having 2 to 4 carbon atoms.

114. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 101 to 113,in which n is 0.

115. A compound of Formula (N):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   W³ is nitrogen or CH;    -   Z¹ is oxygen or sulfur;    -   each of R¹¹ and R¹² is independently hydrogen, halogen,        hydroxyl, nitro, amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl,        or C₁₋₈ haloalkoxy′    -   each of R¹³ and R¹⁴ is independently hydrogen or C₁₋₈ alkyl;    -   A¹ is a 5-membered heterocycle which is pyrazole or thiophene,        in which the 5-membered heterocycle is unsubstituted or        substituted with halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl,        C₁₋₈ alkoxy, C₁₋₈ haloalkyl, or C₁₋₈ haloalkoxy;    -   m is 2, 3, or 4;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

116. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 115, in which W³represents CH.

117. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 115 or 116, which A¹represents pyrazole which may have a substituent selected from the groupconsisting of a halogen atom, a hydroxyl group, a nitro group, an aminogroup, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and ahalogen substituent, or an alkoxy group having 1 to 8 carbon atoms and ahalogen substituent.

118. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 115 to 117,in which m is 2 or 3.

119. A compound of Formula (O):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of W¹ and W² independently is CH or nitrogen;    -   X is NR⁵ or CR⁶R⁷; wherein R⁵ is hydrogen, C₁₋₈ alkyl, C₁₋₈        haloalkyl, C₁₋₈ alkyl substituted with C₁₋₈ alkoxy, C₃₋₇        cycloalkyl, C₁₋₈ alkyl substituted with C₃₋₇ cycloalkyl, C₁₋₈        alkyl substituted with phenyl, C₂₋₈ acyl, or C₂₋₈ alkenyl, and        each of R⁶ and R⁷ independently is hydrogen or C₁₋₈ alkyl;    -   Y is (CR⁸R⁹)_(r), wherein each of R⁸ and R⁹ independently is        hydrogen or C₁₋₈ alkyl, and r is 1, 2, 3, or 4; or    -   X and Y are combined to form CR¹⁰═CR¹¹ or ethynylene, wherein        each of R¹⁰ and R¹¹ independently is hydrogen or C₁₋₈ alkyl;    -   G, when bond a is present, is 0, S or CR¹²R¹³, wherein each of        R¹² and R¹³ independently is hydrogen or C₁₋₈ alkyl; G, when        bond a is absent, is OH;    -   A is a five-membered heterocyclic ring which is thiazole,        oxazole, imidazole, pyrazole, thiophene, furan, or pyrrole,        wherein the heterocyclic ring is unsubstituted or substituted        with C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl, nitro, C₂₋₈        acyl, C₆₋₁₀ aryl, or a five-membered or six-membered        heterocyclic group;    -   B is a C₁₋₈ alkylene, C₂₋₈ alkenylene or C₂₋₈ alkynylene chain,        wherein the chain is unsubstituted or substituted with C₁₋₈        alkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, or halogen;    -   each of R¹ and R² independently is hydrogen, C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl,        C₁₋₈ haloalkoxy, hydroxyl, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a        five-membered or six-membered heterocyclic group;    -   each of R³ and R⁴ independently is hydrogen or C₁₋₈ alkyl;    -   m is 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

120. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119, wherein each of W¹and AP is CH.

121. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 or 120, wherein X isCR⁶R⁷.

122. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 or 120, wherein X isCH₂

123. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 or 120, wherein X isNR⁵.

124. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 or 120, wherein X isNH.

125. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 or 120, wherein X isNR³, and R⁵ is C₁₋₈ alkyl.

126. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 125,wherein Y is CH₂.

127. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 126,wherein Z is carboxyl.

128. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 127,wherein A is thiazole, which can be substituted with a substituentselected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₃alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted with halogen, C₁₋₈alkoxy substituted with halogen, hydroxyl, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl,and a five-membered or six-membered heterocyclic group.

129. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 128,wherein B is ethylene chain.

130. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 129,wherein each of R¹ and R² independently is hydrogen, CEs alkyl, C₂₋₃alkenyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted with halogen, orC₁₋₈ alkoxy substituted with halogen.

131. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 129,wherein each of R¹ and R² independently is hydrogen, C₁₋₈ alkyl,halogen, or C₁₋₈ alkyl substituted with halogen.

132. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 131,wherein each of R³ and R⁴ is hydrogen.

133. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 119 to 132,wherein m is 0.

134. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 to 133, wherein bonda is absent and G is OH.

135. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 119 to 133, wherein bonda is present and G is oxygen.

136. A compound of Formula (P):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   G^(a), when bond a is present, is O, S or CH₂; G^(a), when bond        a is absent, is OH.    -   A^(a) is five-membered heterocyclic ring which is thiazole,        oxazole, or thiophene, wherein the five-membered heterocyclic        ring is unsubstituted or is substituted with C₁₋₈ alkyl, C₁₋₈        alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   B^(a) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain;    -   each of R^(1a) and R^(2a) independently is hydrogen, C₁₋₈ alkyl,        C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

137. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 136, wherein A^(a) isthiazole, which can be substituted with a substituent selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkylsubstituted with halogen, C₁₋₆ alkoxy substituted with halogen,hydroxyl, nitro, and C₂₋₈ acyl.

138. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 136 or 137, wherein B³is ethylene chain.

139. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 136 to 138,wherein each of R^(1a) and R^(2a) independently is hydrogen, C₁₋₈ alkyl,C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted with halogen, or C₁₋₈alkoxy substituted with halogen.

140. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 136 to 139,wherein bond a is absent and G^(a) is OH.

141. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 136 to 139,wherein bond a is present and G^(a) is oxygen.

142. A compound of Formula (Q):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   G^(b), when bond a is present, is O, S or CH₂; G^(b), when bond        a is absent, is OH;    -   A^(b) is five-membered heterocyclic ring which is thiazole,        oxazole, or thiophene, wherein the five-membered heterocyclic        ring is unsubstituted or is substituted with C₁₋₈ alkyl, C₁₋₈        alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   B^(b) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain;    -   each of R^(1b) and R^(2b) independently is hydrogen, C₁₋₈ alkyl,        C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl,        nitro, or C₂₋₈ acyl;    -   R^(3b) is hydrogen or C₁₋₈ alkyl;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

143. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 142, wherein A^(b) isthiazole, which is substituted with a substituent selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, halogen, C₁₋₈ alkylsubstituted with halogen, C₁₋₈ alkoxy substituted with halogen,hydroxyl, nitro, and C₂₋₈ acyl.

144. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 142 or 143, whereinB^(b) is ethylene chain.

145. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 142 to 144,wherein each of R^(1b) and R^(2b) independently is hydrogen, C₁₋₈ alkyl,C₁₋₈ alkoxy, halogen, C₁₋₈ alkyl substituted with halogen, or C₁₋₈alkoxy substituted with halogen.

146. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 142 to 145,wherein bond a is absent and G^(b) is OH.

147. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 142 to 145,wherein bond a is present and G^(b) is oxygen.

148. A compound of Formula (R):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   each of W¹ and W² is independently CH or N;    -   X is NR³ or CR⁴R⁵, in which R³ is C₁₋₈ alkyl, C₁₋₈ haloalkyl,        C₁₋₈ alkyl substituted with C₁₋₈ alkoxy, C₁₋₈ alkyl substituted        with a 3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with a        phenyl group, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   each of R⁴ and R⁵ is independently hydrogen or C₁₋₈ alkyl;    -   Y is (CR⁶R⁷)_(r), in which each of R⁶ and R⁷ is independently        hydrogen or C₁₋₈ alkyl and r is 1, 2, 3, or 4;    -   A is a 5 or 6-membered heterocyclic group which is thiazole,        oxazole, imidazole, pyrazole, thiophene, furan, pyrrole,        pyridine or pyrimidine, or a phenyl group, wherein the 5 or        6-membered heterocyclic group or phenyl group is unsubstituted        or substituted with C₁₋₈ alkyl, 3-7 membered cycloalkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxyl, C₁₋₈ alkyl group        substituted with a 3-7 membered cycloalkyl group, C₁₋₈        haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5 or 6-membered        heterocyclic group, aralkyl group comprising a C₆₋₁₀ aryl group        and a C₁₋₈ alkyl group, or C₁₋₈ alkyl group substituted with a 5        or 6-membered heterocyclic group;    -   B is a bond or C₁₋₈ alkylene which is unsubstituted or        substituted with C₁₋₈ alkyl, a 3-7 membered cycloalkyl group,        C₁₋₈ alkoxy or a halogen, and which may have a double bond or        triple bond when the carbon number of the alkylene chain is 2 or        more;    -   D is N or CH;    -   E is O or S;    -   each of R¹ and R² is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈        haloalkoxy, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a 5 or 6-membered        heterocyclic group;    -   m 0, 1, 2, or 3;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

149. A compound of Formula (S):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   A¹ is a 5 or 6-membered heterocyclic group which is thiazole,        oxazole, pyridine or pyrimidine, or a phenyl group, wherein the        5 or 6-membered heterocyclic group or phenyl group is        unsubstituted or substituted with C₁₋₈ alkyl or C₁₋₈ haloalkyl;    -   B¹ is C₂₋₄ alkylene;    -   each of R¹¹ and R¹² is independently H, C₁₋₈ alkyl, halogen, or        C₁₋₈ haloalkyl;    -   R¹³ is C₁₋₈ alkyl or C₁₋₈ haloalkyl, optionally wherein the N to        which R¹³ is attached is attached to the 6th position of        benzisoxazole;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

150. A compound of Formula (T):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   B² is C₂₋₄ alkylene;    -   R²⁰ is C₁₋₈ alkyl;    -   each of R²¹ and R²² is independently H, C₁₋₈ alkyl, halogen, or        C₁₋₈ haloalkyl;    -   R²³ is C₁₋₃ alkyl or C₁₋₃ haloalkyl, optionally wherein the N to        which R²³ is attached is attached to the 6th position of        benzisoxazole;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; each R^(X6) and R^(X7) is independently H, C₁₋₆        alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and    -   n is 0, 1, 2, 3, or 4.

151. A compound of Formula (U):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₃ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R² is hydrogen, C₁₋₈ alkyl, C₂₋₃ alkenyl, C₁₋₈ alkyl having a 3-        to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl        group having a C₁₋₈ alkoxy substituent, C₂₋₃ acyl, C₆₋₁₀ aryl,        or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R³, R⁴, R⁵ and R⁶ independently is hydrogen, C₁₋₈ alkyl,        or C₁₋₈ haloalkyl;    -   X is oxygen, sulfur or NR⁷; where R⁷ is hydrogen, C₁₋₈ alkyl,        C₁₋₈ haloalkyl, an aralkyl group having a C₆₋₁₀ aryl moiety and        a C₁₋₈ alkylene moiety, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   Y is oxygen, sulfur, NR⁸ or a bond, where R^(a) is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   p is 0 or 1;    -   A, when bond a is present, is oxygen CH₂, N—NH₂ or N—OR⁹, where        R⁹ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, C₂₋₈        alkenyl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a        C₁₋₈ alkylene moiety; A, when bond a is absent, is OH;    -   B is, in the case of p=1, a benzene ring having or not having a        substituent which is halogen, hydroxyl, nitro, amino, C₁₋₈        alkyl, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₃ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, or an aralkyl        group having a C₆₋₁₀ aryl moiety and a C₁-C₈ alkylene moiety of        1-8 carbon atoms, and, in the case of p=0, a condensed ring        which is indole, benzofuran, benzisoxazole or        1,2-benzisothiazole, in which said condensed ring has or does        not have a substituent which is    -   halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl group, C₃₋₇        cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl        having a 3- to 7-membered cycloalkyl substituent, C₁₋₈        haloalkyl, C₁₋₈ alkyl having a C₁-C₈ alkoxy substituent, C₁₋₈        haloalkoxy group, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   Y is bonded to the benzene ring of B;    -   (C(R³)(R⁴))_(m) is bonded to the condensed ring of B at its        3-position;    -   m is an integer of 1 to 4;    -   n is 0, 1, 2, 3, 4, or 5;    -   Y is a bond in the case of n=0;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

152. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 151, wherein bond a isabsent and A is OH.

153. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 151, wherein bond a ispresent and A is oxygen.

154. A compound of Formula (V)

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R¹² is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ alkyl having a        3- to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈ acyl, C₆₋₁₀        aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R¹³, R¹⁴, R¹⁵ and R¹⁶ independently is hydrogen, C₁₋₈        alkyl, or C₁₋₈ haloalkyl;    -   Y¹ is oxygen, sulfur, NR¹⁸ or a bond, where R¹⁸ is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   A¹, when bond a is present, is oxygen CH₂, N—NH₂ or N—OR¹⁹,        where R¹⁹ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl,        C₂₋₈ alkenyl, or an aralkyl group having a C₆₋₁₀ aryl moiety and        a C₁₋₈ alkylene moiety; A¹, when bond a is absent, is OH;    -   Q¹ is hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl        group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   r is 1, 2, 3, or 4;    -   s is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

155. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 154, wherein bond a isabsent and A¹ is OH.

156. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 154, wherein bond a ispresent and A¹ is oxygen.

157. A compound of Formula (N):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano,        carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈        alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered        cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈        alkoxy substituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl        group, a 5- or 6-membered heterocyclic group, an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, or a C₁₋₈        alkyl group having a 5- or 6-membered heterocyclic substituent;    -   R²² is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ alkyl having a        3- to 7-membered cycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈        alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈ acyl, C₆₋₁₀        aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈        alkylene moiety;    -   each of R²³, R²⁴, R²⁵ and R²⁶ independently is hydrogen, C₁₋₈        alkyl, or C₁₋₈ haloalkyl;    -   Y² is oxygen, sulfur, NR²⁸ or a bond, where R²⁸ is hydrogen,        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl;    -   Q² is hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl        group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,        C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,        C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent,        C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group        having a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety;    -   t is 1, 2, 3, or 4;    -   u is 1, 2, 3, 4, or 5;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle;    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

158. A compound of Formula (X):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl; Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CD₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

159. A compound of Formula (Y):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CD₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

160. A compound of Formula (Z):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   Q¹ is CH or N;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 1 or 2;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃₋₆ cycloalkyl;    -   each R²⁰ is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or        C₁₋₄ alkoxy;    -   R³ is CH₃ or CD₃;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

161. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 160,wherein R³ is CH₃.

162. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 161,wherein Q¹ is CH.

163. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 161,wherein Q¹N.

164. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is halogen, —C₁-C₄-alkyl, —C₁-C₄-haloalkyl,—C₁-C₄-haloalkoxy, —S(C₁-C₄-alkyl), or furanyl, wherein the furanyl canbe optionally substituted with —C₁-C₄-alkyl.

165. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is halogen, —CH₃, —C₁-haloalkyl, —C₁-haloalkoxy, —SCH₃, orfuranyl, wherein the furanyl can be optionally substituted with —CH₃.

166. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is halogen, —CH₃, —C₁-haloalkyl, —C₁-haloalkoxy, or —SCH₃.

167. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is chloro, unsubstituted furanyl, —CH₃, —CF₃, —OCF₃, —OCHF₂,or —SCH₃.

168. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is —CF₃ or —OCF₃.

169. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R² is —CF₃.

170. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 169,wherein R¹ is hydrogen or halogen.

171. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 170,wherein R¹ is hydrogen or fluoro.

172. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 171,wherein each R²⁰ is independently hydrogen or halogen.

173. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 171,wherein R²⁰ is hydrogen or fluoro.

174. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R¹ is hydrogen or fluoro, R² is C₁-C₄-haloalkyl orC₁-C₄-haloalkoxy, R²⁰ is hydrogen, and x is an integer having a value of1.

175. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 158 to 163,wherein R¹ is hydrogen, R² is trifluoro methyl or trifluoromethoxy, R²⁰is hydrogen, and x is an integer having a value of 1.

176. A compound of Formula (AA):

-   -   or a pharmaceutically acceptable salt, solvate, ester, amide, or        prodrug thereof, wherein:    -   L is (CH₂)₅, which is unsubstituted or substituted by one methyl        group;    -   R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl;    -   R² is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),        SO₂(C₁₋₄-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered        heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl and heteroaryl are        unsubstituted or substituted with halogen, OH, CN, C₁₋₄ alkyl,        formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or        3;    -   x is 0 or 1;    -   R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄        haloalkyl, or C₃-6 cycloalkyl;    -   R³ is C₁₋₄ haloalkyl, NO₂, CN, halogen, or C(O)O(C₁₋₄ alkyl);    -   R²⁰ is hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄ alkoxy;    -   R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

-   -   each R^(X4) and R^(X5) is independently alkyl, aryl, or        heteroaryl; or alternatively, R^(X4) and R^(X5) together with        the carbon atom to which R^(X4) and R^(X5) are attached form a        heterocycle; and    -   each R^(X6) and R^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl.

177. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 176, which has theformula

178. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 176, which has theformula

179. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 178,wherein R³ is halomethyl, CN or halogen.

180. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 178,wherein R³ is CF₃, Cl or CN.

181. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 180,wherein R² is hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄-haloalkyl, C₁-C₄-haloalkyl, S(C₁-C₄-alkyl), or furanyl, whereinthe furanyl can be optionally substituted with C₁-C₄-alkyl; and x is 0or 1.

182. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 180,wherein R² is H, halogen, CN, CH₃, halomethyl, halomethoxy, methoxy orfuranyl, wherein the furanyl can be optionally substituted with CH₃; andR²⁰ is methyl or halogen.

183. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 180,wherein R² is H, F, C, CN, CF₃, OCF₃ or furanyl; and x is 0.

184. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 183,wherein R¹ is hydrogen.

185. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 176 to 184,wherein R¹ is hydrogen or fluoro.

186. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 185,wherein R^(X) is CH₂OH, COH, or COOCH₂CONR⁴R⁵.

187. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 186, wherein R^(X) isCH₂OH.

188. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 187,when depending from any one of embodiments 1 to 151, wherein n is 0.

189. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of any one of embodiments 1 to 187,when depending from any one of embodiments 1 to 151, wherein n is 1.

190. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

191. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

192. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

193. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 1, which is

pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

194. The compound or pharmaceutically acceptable salt, solvate, ester,amide, or prodrug of the compound of embodiment 158, which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

195. A compound which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

196. A compound which is

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

197. A compound selected from compounds shown in Table 1, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

198. A compound selected from compounds shown in Table 2, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

199. A compound selected from compounds shown in Table 3, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

200. A compound selected from compounds shown in Table 4, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

201. A compound selected from compounds shown in Table 5, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

202. A compound selected from compounds shown in Table 6, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

203. A compound selected from compounds shown in Table 7, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

204. A compound selected from compounds shown in Table 8, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

205. A compound selected from compounds shown in Table 9, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

206. A compound selected from compounds shown in Table 10, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof

207. A compound selected from compounds shown in Table 11, orpharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof.

208. The compound or pharmaceutically acceptable salt of the compound ofany one of embodiments 1 to 207.

209. The pharmaceutically acceptable salt of the compound of any one ofembodiments 1 to 207, which is an alkali metal salt, optionally which isa sodium or a potassium salt.

210. A pharmaceutical composition comprising the compound orpharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of any one of embodiments 1 to 207 and a pharmaceuticallyacceptable carrier or vehicle.

211. The pharmaceutical composition of embodiment 210, furthercomprising a second therapeutically active agent.

212. The pharmaceutical composition of embodiment 211, wherein thesecond therapeutically active agent is a lipid lowering drug, statin, acholesterol absorption inhibitor, an antibody against PCSK9, an siRNAPCSK9, an anti-fibrotic agent, a thyroid hormone, a selective thyroidreceptor-β agonist,apoptosis signal-regulating kinase 1 (ASK1)inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, an integrinantagonist, or a non-steroidal Farnesoid X receptor (FXR) agonist.

213. The pharmaceutical composition of embodiment 212, wherein the lipidlowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate,ciprofibrate, clinofibrate, etofylline, pirifibrate, simfibrate,tocofibrate, or pemafibrate; the statin is atorvastatin, simvastatin,pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin,mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; the cholesterol absorption inhibitor is ezetimibe; the antibodyagainst PCSK9 is evolocumab alirocumab, bococizumab, 1D05-IgG2, RG7652,LY3015014, or LGT-209; the siRNA PCSK9 is inclisiran; the anti-fibroticagent is nitazoxamide, tizoxanide, or tizoxanide glucuronide, or apharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; the selective thyroid receptor-β agonist is VK2809, MGL-3196,MGL-3745, SKL-14763, sobetirome, BCT304, ZYT1, MB-0781, or eprotirome;the ASK1 inhibitor is selonsertib; the ACC inhibitor is firsocostat; theintegrin antagonist is an α5β1 inhibitor or a pan integrin inhibitor; orthe FXR agonist is cilofexor.

214. A method for treating or preventing a liver disorder, dyslipidemia,dyslipoproteinemia, a renal disease, a disorder of glucose metabolism, adisorder of lipid metabolism, a disorder of glucid metabolism, acardiovascular disease, a vascular disease, a metabolic syndrome, acomplication associated with metabolic syndrome, a PPAR-associateddisorder, septicemia, a thrombotic disorder, obesity, diabeticnephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, acerebrovascular disease, a disorder related to neovascularization,hypertension, cancer, inflammation, an inflammatory disease, aneurodegenerative disease, an autoimmune disease, a neoplastic disease,muscle atrophy, cholestasis, mitochondrial dysfunction, an oculardisease, a lysosomal storage disease, a kidney disease, or impotence,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of any one of embodiments 1 to207.

215. The method of embodiment 214, wherein the liver disorder involvespathological disruption, inflammation, degeneration, apoptosis, orproliferation of liver cells.

216. The method of embodiment 214, wherein the liver disorder is liverfibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD)or non-alcoholic steatohepatitis (NASH).

217. The method of embodiment 214, wherein the dyslipidemia ishyperlipidemia or an abnormally low concentration of high densitylipoprotein cholesterol (HDL-C) in the subject's blood plasma or bloodserum.

218. The method of embodiment 217, wherein the hyperlipidemia ishypercholesterolemia, familial hypercholesterolemia,hypertriglyceridemia, or familial combined hyperlipidemia.

219. The method of embodiment 217, wherein the hyperlipidemia ischaracterized by: an abnormally reduced or deficient lipoprotein lipaselevel or activity in the subject's blood plasma or blood serum, or anabnormally high concentration of ketone bodies, lipoprotein(a)cholesterol (Lp(a)-C), low density lipoprotein (LDL), very low densitylipoproteins cholesterol (VLDL-C) or non-esterified fatty acids in thesubject's blood plasma or blood serum.

220. The method of embodiment 219, wherein the reduced or deficientlipoprotein lipase level or activity is a result of a mutation in a geneencoding a lipoprotein lipase.

221. The method of embodiment 214, wherein the dyslipoproteinemia ischaracterized by an abnormally high concentration of LDL, apolipoprotein(a) or VLDL in a subject's blood plasma or blood serum, or an abnormallylow concentration of high density lipoprotein (HDL) or lipoproteinlipase in a subject's blood plasma or blood serum.

222. The method of embodiment 221, wherein the abnormally lowconcentration of the lipoprotein lipase is associated with: alipoprotein lipase mutation, hypoalphalipoproteinemia, a lipoproteinabnormality associated with diabetes, a lipoprotein abnormalityassociated with obesity, a lipoprotein abnormality associated withAlzheimer's disease, or familial combined hyperlipidemia.

223. The method of embodiment 214, wherein the renal disease is aglomerular disease, a tubular disease, a tubulointerstitial disease,acute or rapidly progressive renal failure, chronic renal failure,nephrolithiasis, or a tumor.

224. The method of embodiment 223, wherein: the glomerular disease is anacute glomerulonephritis, a chronic glomerulonephritis, a rapidlyprogressive glomerulonephritis, a nephrotic syndrome, a focalproliferative glomerulonephritis, a glomerular lesion associated withsystemic disease, Goodpasture syndrome, multiple myeloma, diabetes,neoplasia, sickle cell disease or a chronic inflammatory disease; thetubular disease is an acute tubular necrosis, an acute renal failure, apolycystic renal disease, medullary sponge kidney, a medullary cysticdisease, nephrogenic diabetes, or a renal tubular acidosis; thetubulointerstitial disease is pyelonephritis, a drug- or toxin-inducedtubulointerstitial nephritis, a hypercalcemic nephropathy, or ahypokalemic nephropathy; or the tumor is renal cell carcinoma ornephroblastoma.

225. The method of embodiment 224, wherein the glomerular lesionassociated with systemic disease is systemic lupus erythematosus.

226. The method of embodiment 214, wherein the renal disease ishypertension, nephrosclerosis, microangiopathic hemolytic anemia,atheroembolic renal disease, diffuse cortical necrosis, or a renalinfarct.

227. The method of embodiment 226, wherein the hypertension is anessential hypertension, hyperpiesa, hyperpiersis, a malignanthypertension, a secondary hypertension, or a white-coat hypertension.

228. The method of embodiment 214, wherein the disorder of glucosemetabolism is an impaired glucose tolerance; an insulin resistance; aninsulin resistance-related breast, colon or prostate cancer; diabetes;pancreatitis; hypertension; polycystic ovarian disease; or an abnormallyhigh concentration of blood insulin or glucose in the subject's bloodplasma or blood serum.

229. The method of embodiment 228, wherein the diabetes is non-insulindependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus(IDDM), gestational diabetes mellitus (GDM), or maturity onset diabetesof the young (MODY).

230. The method of embodiment 214, wherein the vascular disease or thecardiovascular disease is a peripheral vascular disease, a coronaryheart disease, stroke, restenosis, arteriosclerosis, ischemia, anendothelium dysfunction, an ischemia-reperfusion injury, a myocardialinfarction, or a cerebral infarction.

231. The method of embodiment 214, wherein the PPAR-associated disorderis rheumatoid arthritis, multiple sclerosis, psoriasis, an inflammatorybowel disease, breast cancer, colon cancer, or prostate cancer.

232. The method of embodiment 214, wherein the PPAR-associated disorderis a vascular disease, a muscular disease, a demyelinating disease, amuscle structure disorder, a neuronal activation disorder, a musclefatigue disorder, a muscle mass disorder, a mitochondrial disease, amitochondrial dysfunction, a beta oxidation disease, or a metabolicdisease.

233. The method of embodiment 232, wherein: the muscular disease is amuscular dystrophy disease; the demyelinating disease is multiplesclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease,encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, orGuillian-Barre syndrome; the muscle structure disorder is Bethlemmyopathy, central core disease, congenital fiber type disproportion,distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD,facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a musclesodium channel disorder, myotonic chondrodystrophy, myotonic dystrophy,myotubular myopathy, nemaline body disease, oculopharyngeal MD, orstress urinary incontinence; the neuronal activation disorder isamyotrophic lateral sclerosis, Charcot-Marie-Tooth disease,Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis,myasthenia gravis, a nerve lesion, peripheral neuropathy, spinalmuscular atrophy, tardy ulnar nerve palsy, or toxic myoneural disorder;the muscle fatigue disorder is chronic fatigue syndrome, diabetes (typeI or II), a glycogen storage disease, fibromyalgia, Friedreich's ataxia,intermittent claudication, lipid storage myopathy, MELAS (mitochondrialencephalopathy, lactic acidosis, and stroke-like episodes) syndrome,mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; the musclemass disorder is cachexia, cartilage degeneration, cerebral palsy,compartment syndrome, critical illness myopathy, inclusion bodymyositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, orsystemic lupus erythematosus; the mitochondrial disease is Alpers'sdisease, chronic progressive external ophthalmoplegia (CPEO),Kearns-Sayra syndrome (KSS), Leber hereditary optic neuropathy (LHON),MELAS, myoclonic epilepsy and ragged-red fiber disease (MERRF),neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, Pearsonsyndrome, mitochondrial malfunction, or a mitochondrial loss offunctionality; the beta oxidation disease is systemic carnitinetransporter, carnitine palmitoyltransferase (CPT) II deficiency, verylong-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency,trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase(MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency,or riboflavin-responsive disorders of β-oxidation (RR-MADD); or themetabolic disease is hyperlipidemia, dyslipidemia,hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia,LDL hypercholesterolemia, HLD non-cholesterolemia, VLDLhyperproteinemia, dyslipoproteinemia, apolipoprotein A-1hypoproteinemia, atherosclerosis, a disease of arterial sclerosis, adisease of cardiovascular system, cerebrovascular disease, peripheralcirculatory disease, metabolic syndrome, syndrome X, obesity, diabetes,type I diabetes, type II diabetes, hyperglycemia, insulin resistance,impaired glucose tolerance, hyperinsulinism, a diabetic complication,cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension,non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), a thrombus, Alzheimer disease, a neurodegenerative disease, ademyelinating disease, multiple sclerosis, adrenal leukodystrophy,dermatitis, psoriasis, acne, skin aging, trichosis, inflammation,arthritis, asthma, hypersensitive intestine syndrome, ulcerativecolitis, Crohn's disease, or pancreatitis.

234. The method of embodiment 233, wherein the muscular dystrophydisease is Duchenne muscular dystrophy, Becker muscular dystrophy, alimb-girdle muscular dystrophy, congenital muscular dystrophy,facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy,oculopharyngeal muscular dystrophy, distal muscular dystrophy, orEmery-Dreifuss muscular dystrophy.

235. The method of embodiment 214, wherein the PPAR-associated disorderis an abnormally low concentration of HDL, an abnormally lowconcentration of apolipoprotein A-1 (apo A-1), an abnormally highconcentration of VLDL-C, an abnormally high concentration of low densitylipoprotein cholesterol (LDL-C), an abnormally high concentration oftriglyceride, an abnormally high concentration of apolipoprotein B (apoB), an abnormally high concentration of apolipoprotein C-III (apo C-III)or an abnormally reduced ratio of post-heparin hepatic lipase tolipoprotein lipase activity in the subject's blood plasma or bloodserum.

236. The method of embodiment 214, wherein the PPAR-associated disorderis an abnormally high concentration of HDL or an abnormally lowconcentration of apo A-1 in the subject's lymph or cerebral fluid.

237. The method of embodiment 214, wherein the obesity is abdominalobesity.

238. The method of embodiment 214, wherein the cerebrovascular diseaseis cerebral ischemia.

239. The method of embodiment 214, wherein, the disorder related toneovascularization is retinopathy or diabetes.

240. The method of embodiment 214, wherein the cancer is a human sarcomaor human carcinoma.

241. The method of embodiment 214, wherein the cancer is fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,bone cancer, breast cancer, ovarian cancer, prostate cancer, esophagealcancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinoma,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acutelymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia,acute promyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocytic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, hairy cellleukemia, lymphoblastic leukemia, myelogenous leukemia,lymphocyticleukemia, myelocytic leukemia, polycythemia vera, multiplemyeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma,Waldenstrom's macroglobulinemia, or a heavy chain disease.

242. The method of embodiment 241, wherein the leukemia is acute orchronic lymphoblastic leukemia, myelogenous leukemia,lymphocyticleukemia, lymphocytic leukemia, or myelocytic leukemia.

243. The method of embodiment 242, wherein the myelocytic leukemia isacute and is myeloblastic, promyclocytic, myelomonocytic, monocytic orerythroleukemia.

244. The method of embodiment 242, wherein the lymphoma is Hodgkin'slymphoma or non-Hodgkin's lymphoma.

245. The method of embodiment 214, wherein the inflammatory disease ismultiple sclerosis, a chronic inflammatory disorder of a joint,arthritis, a respiratory distress syndrome, an inflammatory boweldisease, an inflammatory lung disorder, an inflammatory disorder, aninflammatory disorder of the gum, tuberculosis, leprosy, an inflammatorydisease of the kidney, an inflammatory disorder of the skin, aninflammatory disease of the central nervous system, a systemic lupuserythematosus (SLE) or an inflammatory disease of the heart.

246. The method of embodiment 245, wherein: the arthritis is rheumatoidarthritis or osteoarthritis; the inflammatory bowel disease is ileitis,ulcerative colitis or Crohn's disease; the inflammatory lung disorder isasthma or chronic obstructive airway disease; the inflammatory disorderof the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis,sympathic ophthalmitis or endophthalmitis; the inflammatory disorder ofthe gum is periodontitis or gingivitis; the inflammatory disease of thekidney is glomerulonephritis or nephrosis; the inflammatory disorder ofthe skin is acne, sclerodermatitis, psoriasis, eczema, photoaging orwrinkles; the inflammatory disease of the central nervous system isAIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer'sdisease, encephalomyelitis, or viral or autoimmune encephalitis; or theinflammatory disease of the heart is cardiomyopathy.

247. The method of embodiment 214, wherein the neurodegenerative diseaseis Alzheimer's disease or Huntington's disease.

248. The method of embodiment 214, wherein the autoimmune disease isimmune-complex vasculitis, systemic lupus or erythematodes.

249. The method of embodiment 214, wherein, the neoplastic disease iscarcinogenesis.

250. The method of embodiment 214, wherein the cholestasis isintrahepatic cholestatic disease or extrahepatic cholestatic disease.

251. The method of embodiment 250, wherein intrahepatic cholestaticdisease is primary biliary cholangitis (PBC), primary sclerosingcholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC),or Alagille syndrome (AS).

252. The method of embodiment 214, wherein the ocular disease is dryeye, meibomian gland dysfunction, a keratoconjunctiva epithelialdisorder, a corneal epithelial disorder, or a corneal ulcer.

253. The method of embodiment 214, wherein the lysosomal storagedisorder is neuronal ceroid lipofuscinosis, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, multiple system atrophy (MSA), progressive supranuclear palsy(PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB),a disorder of the autophagy pathway, Tay-Sach's disease, Fabry disease,Niemann-Pick disease, Gaucher disease, Hunter syndrome,alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storagedisease, chronic hexosaminidase A deficiency, cystinosis, Danon disease,Farber disease, fucosidosis, galactosialidosis, or Batten disease.

254. The method of embodiment 214, wherein the kidney disease is renalischemia reperfusion injury.

255. The method of embodiment 214, wherein the impotence results fromdamages to a nerve, artery, a smooth muscle, or fibrous tissue;diabetes; kidney disease; alcoholism; multiple sclerosis;atherosclerosis; vascular disease; or neurologic disease.

256. A method for treating or preventing hyperlipemia, hyperlipidemia,hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, ordyslipidemia, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1 to 207.

257. The method of embodiment 256, wherein the hypercholesterolemia ishomozygous familial hypercholesterolemia.

258. A method for treating a subject having or preventing a subject fromhaving an abnormally high concentration in a subject's blood plasma orblood serum of high low-density lipoprotein (LDL), apolipoprotein B (apoB), lipoprotein(a) (Lp(a)), apolipoprotein (a), or very low-densitylipoprotein (VLDL), comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1 to 207.

259. A method for treating a subject having or preventing a subject fromhaving an abnormally low concentration in a subject's blood plasma orblood serum of high-density lipoprotein (HDL), comprising administeringto a subject in need thereof an effective amount of the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of any one of embodiments 1 to 207.

260. A method for treating a subject having or preventing a subject fromhaving an abnormally reduced or deficient lipoprotein lipaseconcentration or activity in a subject's blood plasma or blood serum,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of any one of embodiments 1 to207.

261. The method of embodiment 260, wherein the reduced or deficientlipoprotein lipase level or activity is a result of a mutation in a geneencoding a lipoprotein lipase.

262. A method for treating or preventing hypoalphalipoproteinemia, alipoprotein abnormality associated with diabetes, a lipoproteinabnormality associated with obesity, a lipoprotein abnormalityassociated with Alzheimer's Disease, or familial combinedhyperlipidemia, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1 to 207.

263. A method for reducing in a subject's blood plasma or blood serum anabnormally high concentration of triglyceride, low-density lipoproteincholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C),non-high-density lipoprotein cholesterol, (non-HDL-C), lipoprotein(a)(Lp(a)), apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II orapolipoprotein C-III, comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1 to 207.

264. A method for elevating in a subject's blood plasma or blood seruman abnormally low concentration of a high-density lipoprotein(HDL)-associated protein, HDL-cholesterol, apolipoprotein A-1, orapolipoprotein E, comprising administering to a subject in need thereofan effective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1 to 207.

265. The method of embodiment 264, wherein the HDL-associated protein isapolipoprotein A-1 (apo A-I), apolipoprotein A-II (apo A-II),apolipoprotein A-IV (apo A-IV) or apolipoprotein E (apo E).

266. A method for promoting clearance of triglyceride from a subject'sblood plasma or blood serum, comprising administering to a subject inneed thereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1 to 207.

267. A method for increasing abnormally low glucose metabolism or lipidmetabolism in a subject, comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofany one of embodiments 1 to 207.

268. The method of embodiment 267, wherein the method for increasingabnormally low glucose metabolism increases insulin sensitivity oroxygen consumption of a subject or decreases blood insulin, bloodglucose, or glycated hemoglobin in a subject's blood plasma or bloodserum.

269. The method of embodiment 267, wherein the method for increasingabnormally low lipid metabolism reduces a concentration of LDL or freetriglyceride in a subject's blood plasma or blood serum, or inhibitssaponified or non-saponified fatty acid synthesis.

270. A method for treating or preventing a symptom of a disease selectedfrom inflammation, systemic lupus erythematosus, lupus nephritis, orarthritis, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1 to 207.

271. The method of embodiment 270, wherein the arthritis is adjuvantarthritis or type II collagen-induced arthritis.

272. The method of embodiment 270, wherein the symptom is nephritis,kidney failure, or kidney function reduction.

273. A method for reducing the fat content of meat in livestock,comprising administering to livestock an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of any one of embodiments 1 to 207.

274. A method for reducing cholesterol content of a fowl egg, comprisingadministering to a fowl species an effective amount of the compound orthe pharmaceutically acceptable salt, solvate, ester, amide, or prodrugof the compound of any one of embodiments 1 to 207.

275. A method for treating a subject with acute kidney injury (AKI) orat risk for AKI, comprising administering to the subject (i) aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of any one ofembodiments 1 to 207 or (ii) the pharmaceutical composition ofembodiment 210 or embodiment 211.

276. The method of embodiment 275, wherein the (i) compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound or (ii) pharmaceutical composition is administeredintravenously, optionally wherein the method comprises once dailyintravenous administration, optionally for three days.

277. The method of embodiment 275, wherein the (i) compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound or (ii) pharmaceutical composition is administered orally.

278. The method of any one of embodiments 275 to 277, wherein the AKI issepsis-related AKI.

279. The method of any one of embodiments 275 to 277, wherein the AKI isischemia/reperfusion AKI.

280. The method of any one of embodiments 275 to 277, wherein the AKI isfrom acute interstitial nephritis.

281. The method of any one of embodiments 275 to 277, wherein the AKI isfrom glomerular renal disease.

282. The method of any one of embodiments 275 to 277, wherein the AKI isfrom acute vasculitic renal disease.

283. The method of any one of embodiments 275 to 277, wherein the AKI isfrom ischemia.

284. The method of any one of embodiments 275 to 277, wherein the AKI isfrom toxic injury.

285. The method of any one of embodiments 275 to 277, wherein the AKI isfrom prerenal azotemia.

286. The method of any one of embodiments 275 to 277, wherein the AKI isfrom acute postrenal destructive nephropathy.

287. The method of any one of embodiments 275 to 277, wherein the AKI isfrom diabetes.

288. The method of any one of embodiments 275 to 277, wherein the AKI isfrom underlying renal insufficiency.

289. The method of any one of embodiments 275 to 277, wherein the AKI isfrom nephritic syndrome.

290. The method of any one of embodiments 275 to 277, wherein the AKI isfrom atherosclerotic disease.

291. The method of any one of embodiments 275 to 277, wherein the AKI isfrom hypotension.

292. The method of any one of embodiments 275 to 277, wherein the AKI isfrom hypoxia.

293. The method of any one of embodiments 275 to 277, wherein the AKI isfrom myoglobinuria-hematuria.

294. The method of any one of embodiments 275 to 277, wherein the AKI isfrom liver disease.

295. The method of any one of embodiments 275 to 277, wherein the AKI issecondary to a viral infection, optionally wherein the viral infectionis COVID-19.

296. The method of embodiment 295, wherein the subject has a viralinfection, optionally wherein the viral infection is COVID-19.

297. The method of 275 to 278, wherein the subject has sepsis.

298. The method of embodiment 296, wherein the sepsis is associated witha gram-negative bacterial infection.

299. The method of embodiment 297 or embodiment 298, wherein the subjecthas an intra-abdominal cavity infection.

300. The method of embodiment 297 or embodiment 298, wherein the subjecthas urosepsis.

301. The method of any one of embodiments 275 to 300, wherein thesubject is elderly.

302. The method of any one of embodiments 275 to 301, wherein thesubject is a surgical patient.

303. The method of embodiment 302, wherein the surgical patient has hada cardiovascular surgery, optionally which is a coronary artery bypassgraft (CABG) surgery and/or heart valve surgery.

304. The method of any one of embodiments 275 to 300, wherein thesubject is pregnant.

305. The method of any one of embodiments 275 to 304, wherein thesubject has been exposed to a nephrotoxic agent.

306. The method of embodiment 305, wherein the nephrotoxic agentcomprises cisplatin, gentamicin, cephaloridine, cyclosporine,amphotericin, carbon tetrachloride, trichloroethylene,dichloroacetylene, or a combination thereof.

307. The method of any one of embodiments 275 to 306, wherein thesubject has AKI.

308. The method of embodiment 307, wherein the effective amount iseffective to reduce the severity of the AKI.

309. The method of any one of embodiments 275 to 306, wherein thesubject is at risk for AKI.

310. The method of any one of embodiments 275 to 306, wherein thesubject is at risk for AKI following a cardiovascular surgery,optionally which is a coronary artery bypass graft (CABG) surgery and/orheart valve surgery.

311. The method of embodiment 309 or embodiment 310, wherein theeffective amount is effective to reduce the likelihood that the subjectwill develop AKI.

312. The method of any one of embodiments 309 to 311, wherein theeffective amount is effective to delay the onset of AKI.

313. The method of any one of embodiments 309 to 311, wherein theeffective amount is effective to prevent AKI.

314. The method of any one of embodiments 309 to 311, wherein if thesubject develops AKI, the effective amount is effective to reduce theseverity of the AKI.

315. The method of any one of embodiments 275 to 314, wherein thesubject has a SOFA score of 1 to 4 prior to administration of thecompound or the pharmaceutically acceptable salt, solvate, ester, amideor prodrug of the compound or the pharmaceutical composition.

316. The method of embodiment 315, wherein the subject has a SOFA scoreof 2 to 4 prior to administration.

317. The method of embodiment 315, wherein the subject has a SOFA scoreof 1 prior to administration.

318. The method of embodiment 315, wherein the subject has a SOFA scoreof 2 prior to administration.

319. The method of embodiment 315, wherein the subject has a SOFA scoreof 3 prior to administration.

320. The method of embodiment 315, wherein the subject has a SOFA scoreof 4 prior to administration. 321. The method of any one of embodiments275 to 320, wherein the subject has an endotoxin activity level of >0.6prior to administration.

322. The method of any one of embodiments 275 to 321, wherein theeffective amount is effective to reduce the subject's endotoxin activitylevel.

8. INCORPORATION BY REFERENCE

All publications, patents, patent applications and other documents citedin this application are hereby incorporated by reference in theirentireties for all purposes to the same extent as if each individualpublication, patent, patent application or other document wereindividually indicated to be incorporated by reference for all purposes.In the event that there are any inconsistencies between the teachings ofone or more of the references incorporated herein and the presentdisclosure, the teachings of the present specification are intended.

1. A compound: (II) of Formula (A)

 or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof, wherein: each R¹ and R² is independently —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹and R² together with the carbon atom to which R¹ and R² are attachedform a C₃-C₇ cycloalkyl group; X is —CH₂OH, —COOH, —COH, —COOR³,—COOCH₂CONR⁴R⁵, —SO₃H,

R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or benzyl;each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; oralternatively, R⁴ and R⁵ together with the carbon atom to which R⁴ andR⁵ are attached form a heterocycle; each R⁶ and R⁷ is independently H,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl; and n is 0, 1, 2, 3, or4; (II) of Formula (B):

 or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof, wherein: each R¹ and R² is independently —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or benzyl; or alternatively, R¹and R² together with the carbon atom to which R¹ and R² are attachedform a C₃-C₇ cycloalkyl group: X is —CH₂OH, —COH, —COOCH₂CONR⁴R⁵, —SO₃H,

R³ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, phenyl, or benzyl;each R⁴ and R⁵ is independently alkyl, aryl, or heteroaryl; oralternatively, R⁴ and R⁵ together with the carbon atom to which R⁴ andR⁵ are attached form a heterocycle; each R⁶ and R⁷ is independently H,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl; and n is 0, 1, 2, 3, or4; (III) having the structure:

 or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof; (IV) having the structure:

 or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof; (V) having the structure:

 or a pharmaceutically acceptable salt, solvate, ester, amide, orprodrug thereof; (VI) of Formula (C):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹ is phenyl, naphthyl, pyridyl, thienyl, furyl,quinolyl or benzothienyl, any of which is unsubstituted or substitutedwith C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro,amino, phenyl or pyridyl; R² is C₂₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, 3-7 membered cycloalkyl, C₁₋₈ alkyl substitutedwith a 3-7 membered cycloalkyl, or C₁₋₆ alkyl substituted with phenyl,naphthyl or pyridyl, any of which is unsubstituted or substituted withC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkoxy, C₂₋₈ alkenyl,C₂₋₈ alkynyl, halogen, C₂₋₇ acyl, benzoyl, hydroxyl, nitro, amino,phenyl or pyridyl; A is oxygen, sulfur or NR⁹ in which R⁹ is hydrogen orC₁₋₈ alkyl; X is a C₁₋₈ alkylene chain which is unsubstituted orsubstituted with C₁₋₈ alkyl, C₁₋₈ alkoxy or hydroxyl, and which has 0 or1 double bonds; Y is C(═O), C(═N—OR¹⁰), CH(OR¹¹), CH═CH, C≡C, or C(═CH₂)in which each of R¹⁰ and R¹¹ is hydrogen or C₁₋₈ alkyl; each of R³, R⁴and R⁵ is independently hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈alkoxy, C₁₋₈ haloalkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₂₋₇ acyl,benzoyl, hydroxyl, nitro, amino, phenyl, or pyridyl; optionally whereinat least one of R³, R⁴, and R⁵ is not hydrogen; B is CH or nitrogen; Zis oxygen or sulfur; each of R⁶ and R⁷ is independently hydrogen, C₁₋₈alkyl, or C₁₋₈ haloalkyl; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5),SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (VII) of Formula (D):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of R¹ and R² independently is a hydrogen, ahalogen, nitro, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1 to 3halogens, C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈ alkenyl, C₂₋₈alkynyl, 3-7 membered cycloalkyl, C₁₋₈ alkyl substituted with 3-7membered cycloalkyl, C₆₋₁₀ aryl which is optionally substituted,arylalkyl group which has a C₆₋₁₀ aryl moiety and C₁₋₈ alkyl moiety, aheterocyclic group or a heterocyclic-alkyl group having a C₁₋₈ alkylgroup; each occurrence of R³, R⁴, and R⁵ is independently a hydrogen orC₁₋₈ alkyl; A is an oxygen atom, a sulfur atom, or NR³; each of X¹, X²,and Z independently is C(═O), C(═O)NH, C(═N—OR⁴), CH(OR⁵), NH(C═O),NHSO₂, SO₂NH, CH═CH, C≡C, or a bond; and Y is C₁₋₈ alkylene; R^(X) isCH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (VIII) of Formula (E):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of R¹¹ and R¹² independently is hydrogen,halogen, nitro, hydroxyl, amino, C₁₋₈ alkyl, an C₁₋₈ alkoxy, C₁₋₈haloalkyl group having 1 to 3 halogens, C₁₋₈ haloalkoxy group having 1to 3 halogens, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a 3-7 membered cycloalkyl,C₁₋₈ alkyl having a 3-7 membered cycloalkyl substituent, or phenyl,naphthyl, benzyl, Phenethyl, Pyridyl, thienyl, furyl, quinolyl, orbenzothienyl group which optionally has a substituent which is a halogenatom, nitro, hydroxyl, amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkylhaving 1 to 3 halogens, C₁₋₈ haloalkoxy having 1 to 3 halogens, C₂₋₈alkenyl, C₂₋₈ alkynyl, 3-7 membered cycloalkyl group, C₁₋₈ alkyl grouphaving a 3-7 membered cycloalkyl substituent, phenyl or pyridyl; each ofX¹ and Z¹ independently is C(═O), C(═O)NH, C(═N—OR¹⁴), CH(OR¹⁵),NH(C═O), NHSO₂, SO₂NH, CH═CH, C≡C, or a bond, wherein each of R¹⁴ andR¹⁵ is a hydrogen or C₁₋₈ alkyl; Y¹ is C₁₋₈ alkylene; R^(X) is CH₂OH,COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (IX) of Formula (F):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: A is O, S or NR⁷ in which R7 is hydrogen or C₁₋₈alkyl; B¹ is CW or N in which W is hydrogen or a bond; B² is O, S or NR⁸in which R⁸ is hydrogen or C₁₋₈ alkyl; each of X¹ and X² is O, S, NH,NHC(═O), C(═O), C(═N—OR⁹), CH(OR¹⁰), C═C, C≡C or a bond, wherein each ofR⁹ and R¹⁰ is hydrogen or C₁₋₈ alkyl; Y is C₁₋₈ alkylene, which isunsubstituted or substituted with C₁₋₈ alkyl or C₁₋₈ haloalkyl having1-3 halogens: Z is NH, O or S; R¹ is aryl, which is unsubstituted orsubstituted with C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1-3halogens, hydroxyl, nitro, amino, phenyl, Pyridyl or halogen, or aheterocyclic group having a five to eight membered ring comprising oneto three hetero atoms each of which is independently nitrogen, oxygen orsulfur and the other atoms are carbon, optionally wherein a benzene ringis condensed with the heterocyclic ring; R² is C₂₋₈ alkyl, C₁₋₈haloalkyl having with 1-3 halogens, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₄ alkyl substituted with aryl, which is unsubstituted orsubstituted with C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl having 1-3halogens, hydroxyl, nitro, amino, phenyl, Pyridyl or halogen, or C₁₋₄alkyl substituted with a heterocyclic group having five to eightmembered ring having one to three heteroatoms each of which isindependently nitrogen, oxygen or sulfur; R³ is halogen,trifluoromethyl, C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl; each of R⁴and R⁵ is hydrogen, C₁₋₈ alkyl or C₁₋₈ haloalkyl having 1-3 halogens;each of Z and R³ is attached to the benzene ring, and X² is not attachedto the benzene ring; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (X) of Formula (G):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of R¹ and R⁴, which are the same or different, isa hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acylgroup, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group; R² ishydrogen; R³ is C₁₋₈ alkyl, or R³ is combined with R² to form ═O or═C(R⁷)(R⁸) in which each of R⁷ and R⁸, which are the same or different,is a hydrogen or C₁₋₈ alkyl; each of R⁵ and R⁶, which are the same ordifferent, is a hydrogen atom, C₁₋₈ alkyl, C₁₋₈ haloalkyl; X and Y arethe same or different and each represents CH or N; Z is oxygen orsulfur; A is a 5-membered heterocyclic group which is Pyrazole,thiophene, furan or Pyrrole, wherein the heterocyclic group isunsubstituted or substituted with C₁₋₈ alkyl having a substituent whichis C₁₋₈ alkyl, 3- to 7-membered cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ alkoxy, C₁₋₃ alkyl group substituted with a 3- to 7-memberedcycloalkyl group, C₁₋₈ haloalkyl, C₁₋₃ haloalkoxy, C₆₋₁₀ aryl, 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or 5- or 6-membered heterocyclicgroup; B is a C₁₋₈ alkylene chain which is unsubstituted or substitutedwith C₁₋₈ alkyl, 3- to 7-membered cycloalkyl group, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl or C₁₋₈ haloalkoxy, thealkylene group optionally having a double bond in the case that thealkylene group has 2 to 6 carbon atoms; q is 0, 1, 2, 3, 4, or 5; R^(X)is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XI) of Formula (H):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of R¹¹ and R¹³, which are the same or different,is a hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl: C₁₋₈ haloalkoxy: hydroxyl, nitro, C₂₋₈ acylgroup, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group; R¹² ishydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylgroup substituent, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or a C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; R¹⁴ and R¹⁵ are the same ordifferent and each is a hydrogen atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; X¹is CH or N; Z¹ is oxygen or sulfur; W¹ is oxygen or CH₂ when bond a ispresent and OH when bond a is absent; q is 2, 3, or 4; R^(X) is CH₂OH,COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XII) of Formula (J):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of R²¹ and R²³, which are the same or different,is a hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acylgroup, C₆₋₁₀ aryl, or a 5- or 6-membered heterocyclic group; R²² ishydrogen, C₁₋₈ alkyl, a 3- to 7-membered cycloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylgroup substituent, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or a C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; R²⁴ and R²⁵ are the same ordifferent and each is a hydrogen atom, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; X²is CH or N; Z² is oxygen or sulfur; W² is oxygen or CH₂ when bond a ispresent and OH when bond a is absent; r is 2, 3, or 4; R^(X) is CH₂OH,COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XIII) of Formula (K):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: A is CH or nitrogen; B, when bond a is present, isoxygen or C(R⁸)(R⁹) in which each of R⁸ and R⁹ is independently hydrogenor C₁₋₈ alkyl; B, when bond a is absent, is OH; W¹ is a bond, C(═O), or(C(R¹⁰)(R¹¹))_(m) in which each of R¹⁰ and R¹¹ is independently ahydrogen or C₁₋₈ alkyl group and m is 1, 2, or 3; X and Y differ fromeach other, and each is an oxygen atom, a sulfur atom, a nitrogen atom,or CR¹² in which R¹² is a hydrogen or C₁₋₈ alkyl; Z¹ is a bond, oxygen,sulfur, or C(R¹³)(R¹⁴) in which each of R¹³ and R¹⁴ is independently ahydrogen or C₁₋₈ alkyl; each of R¹, R², and R³, is independently ahydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen,C₁₋₈ haloalkyl; C₁₋₈ haloalkoxy; hydroxyl, nitro, C₂₋₈ acyl group, C₆₋₁₀aryl, or a 5- or 6-membered heterocyclic group; each of R⁴ and R⁵ isindependently hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl; each of R⁶ and R⁷ isindependently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, or C₁₋₈haloalkyl r is 1, 2, 3, 4, or 5; R^(X) is CH₂OH, COH,COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XIV) of Formula (L):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: B, when bond a is present, is oxygen: B, when bond ais absent, is OH; W² is a bond, C(═O), or CH₂; Z² is oxygen or sulfur;each of R²¹, R²², and R²³ is independently a hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl: C₁₋₈haloalkoxy: hydroxyl, nitro, C₂₋₈ acyl group, C₆₋₁₀ aryl, or a 5- or6-membered heterocyclic group; each of R²⁴ and R²⁵ is independentlyhydrogen, C₁₋₈ alkyl C₁₋₈ haloalkyl; R^(X) is CH₂OH, COH,COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XV) of Formula (M):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of W¹ and W² is independently nitrogen or CH; Xis nitrogen or CH; Y is oxygen or sulfur; Z is a bond, oxygen, sulfur orNR⁵, in which R⁵ is hydrogen or C₁₋₈ alkyl; each of R¹ and R² isindependently hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl, 3-to 7-membered cycloalkyl group, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent, C₁₋₈haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, 5- or 6-membered heterocyclicgroup, an aralkyl group having C₆-10 aryl moiety and a C₁₋₈ alkylene, orC₁₋₈ alkyl having a 5- or 6-membered heterocyclic substituent; each ofR³ and R⁴ is independently hydrogen, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; A isa 5-membered heterocycle which is pyrazole, thiophene, furan, isoxazole,isothiazole or pyrrole, in which the 5-membered heterocycle isunsubstituted or substituted with halogen, hydroxyl, nitro, amino, C₁₋₈alkyl, 3- to 7-membered cycloalkyl group, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylsubstituent, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₆₋₁₀ aryl, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and C₁₋₈ alkylene moiety, or C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; B is a bond or C₁₋₈ alkylene whichis unsubstituted or substituted with C₁₋₈ alkyl, 3- to 7-memberedcycloalkyl, C₁₋₈ alkoxy or a halogen substituent, optionally wherein theC₁₋₈ alkylene has a double or triple bond; r is 0, 1, 2, or 3; R^(X) isCH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XVI) of Formula (N):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: W³ is nitrogen or CH; Z¹ is oxygen or sulfur; each ofR¹¹ and R¹² is independently hydrogen, halogen, hydroxyl, nitro, amino,C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, or C₁₋₈ haloalkoxy′ each of R¹³and R¹⁴ is independently hydrogen or C₁₋₈ alkyl: A¹ is a 5-memberedheterocycle which is Pyrazole or thiophene, in which the 5-memberedheterocycle is unsubstituted or substituted with halogen, hydroxyl,nitro, amino, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, or C₁₋₈haloalkoxy; m is 2, 3, or 4; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5),SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XVII) of Formula (O):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of W¹ and W² independently is CH or nitrogen; Xis NR⁵ or CR⁶R⁷; wherein R⁵ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₁₋₈ alkyl substituted with C₁₋₈ alkoxy, C₃₋₇ cycloalkyl, C₁₋₈ alkylsubstituted with C₃₋₇ cycloalkyl, C₁₋₈ alkyl substituted with phenyl,C₂₋₈ acyl, or C₂₋₈ alkenyl, and each of R⁶ and R⁷ independently ishydrogen or C₁₋₈ alkyl; Y is (CR⁸R⁹)_(r), wherein each of R³ and R⁹independently is hydrogen or C₁₋₈ alkyl, and r is 1, 2, 3, or 4; or Xand Y are combined to form CR¹⁰═CR¹¹ or ethynylene, wherein each of R¹⁰and R¹¹ independently is hydrogen or C₁₋₈ alkyl; G, when bond a ispresent, is O, S or CR¹²R¹³, wherein each of R¹² and R¹³ independentlyis hydrogen or C₁₋₈ alkyl; G, when bond a is absent, is OH; A is afive-membered heterocyclic ring which is thiazole, oxazole, imidazole,pyrazole, thiophene, furan, or pyrrole, wherein the heterocyclic ring isunsubstituted or substituted with C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy,hydroxyl, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a five-membered orsix-membered heterocyclic group; B is a C₁₋₈ alkylene, C₂₋₈ alkenyleneor C₂₋₈ alkynylene chain, wherein the chain is unsubstituted orsubstituted with C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, or halogen;each of R¹ and R² independently is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy,hydroxyl, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl, or a five-membered orsix-membered heterocyclic group; each of R³ and R⁴ independently ishydrogen or C₁₋₈ alkyl; m is 0, 1, 2, or 3; R^(X) is CH₂OH, COH,COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XVIII) of Formula (P):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: G^(a), when bond a is present, is O, S or CH₂; G^(a),when bond a is absent, is OH; A^(a) is five-membered heterocyclic ringwhich is thiazole, oxazole, or thiophene, wherein the five-memberedheterocyclic ring is unsubstituted or is substituted with C₁₋₈ alkyl,C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl, nitro,or C₂₋₈ acyl; B^(a) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain; each ofR^(1a) and R^(2a) independently is hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl, nitro, or C₂₋₈ acyl;R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XIX) of Formula (Q):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: G^(b), when bond a is present, is O, S or CH₂; G^(b),when bond a is absent, is OH; A^(b) is five-membered heterocyclic ringwhich is thiazole, oxazole, or thiophene, wherein the five-memberedheterocyclic ring is unsubstituted or is substituted with C₁₋₈ alkyl,C₁₋₈ alkoxy, halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, hydroxyl, nitro,or C₂₋₈ acyl; B^(b) is a C₁₋₈ alkylene or C₂₋₈ alkenylene chain; each ofR^(1b) and R^(2b) independently is hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl, C₁₋₃ haloalkoxy, hydroxyl, nitro, or C₂₋₈ acyl;R^(3b) is hydrogen or C₁₋₃ alkyl; R^(X) is CH₂OH, COH,COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XX) of Formula (R):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: each of W¹ and W² is independently CH or N; X is NR³or CR⁴R⁵, in which R³ is C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkylsubstituted with C₁₋₃ alkoxy, C₁₋₈ alkyl substituted with a 3-7 memberedcycloalkyl, C₁₋₈ alkyl substituted with a phenyl group, C₂₋₈ acyl, orC₂₋₈ alkenyl; each of R⁴ and R⁵ is independently hydrogen or C₁₋₈ alkyl;Y is (CR⁶R⁷)_(r), in which each of R⁶ and R⁷ is independently hydrogenor C₁₋₈ alkyl and r is 1, 2, 3, or 4; A is a 5 or 6-memberedheterocyclic group which is thiazole, oxazole, imidazole, pyrazole,thiophene, furan, pyrrole, pyridine or pyrimidine, or a phenyl group,wherein the 5 or 6-membered heterocyclic group or phenyl group isunsubstituted or substituted with C₁₋₃ alkyl, 3-7 membered cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxyl, C₁₋₈ alkyl group substitutedwith a 3-7 membered cycloalkyl group, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy,C₆₋₁₀ aryl, a 5 or 6-membered heterocyclic group, aralkyl groupcomprising a C₆₋₁₀ aryl group and a C₁₋₃ alkyl group, or C₁₋₃ alkylgroup substituted with a 5 or 6-membered heterocyclic group; B is a bondor C₁₋₃ alkylene which is unsubstituted or substituted with C₁₋₃ alkyl,a 3-7 membered cycloalkyl group, C₁₋₈ alkoxy or a halogen, and which mayhave a double bond or triple bond when the carbon number of the alkylenechain is 2 or more; D is N or CH: E is O or S; each of R¹ and R² isindependently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,halogen, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, nitro, C₂₋₈ acyl, C₆₋₁₀ aryl,or a 5 or 6-membered heterocyclic group; m 0, 1, 2, or 3; R^(X) isCH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XXI) of Formula (S):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: A¹ is a 5 or 6-membered heterocyclic group which isthiazole, oxazole, pyridine or pyrimidine, or a phenyl group, whereinthe 5 or 6-membered heterocyclic group or phenyl group is unsubstitutedor substituted with C₁₋₈ alkyl or C₁₋₈ haloalkyl; B¹ is C₂₋₄ alkylene;each of R¹¹ and R¹² is independently H, C₁₋₈ alkyl, halogen, or C₁₋₈haloalkyl; R¹³ is C₁₋₈ alkyl or C₁₋₈ haloalkyl, optionally wherein the Nto which R¹³ is attached is attached to the 6th position ofbenzisoxazole; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XXII) of Formula (T):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: B² is C₂₋₄ alkylene; R²⁰ is C₁₋₈ alkyl; each of R²¹and R²² is independently H, C₁₋₈ alkyl, halogen, or C₁₋₈ haloalkyl; R²³is C₁₋₈ alkyl or C₁₋₈ haloalkyl, optionally wherein the N to which R²³is attached is attached to the 6th position of benzisoxazole; R^(X) isCH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;and n is 0, 1, 2, 3, or 4; (XXIII) of Formula (U):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹ is hydrogen, halogen, hydroxyl, nitro, amino,cyano, carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylsubstituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxysubstituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or a C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; R² is hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,C₁₋₈ haloalkyl, C₁₋₈ alkyl group having a C₁₋₃ alkoxy substituent, C₂₋₈acyl, C₆₋₁₀ aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and aC₁₋₃ alkylene moiety; each of R³, R⁴, R⁵ and R⁶ independently ishydrogen, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; X is oxygen, sulfur or NR⁷;where R⁷ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, an aralkyl grouphaving a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety, C₂₋₈ acyl, orC₂₋₈ alkenyl; Y is oxygen, sulfur, NR⁸ or a bond, where R^(a) ishydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, or C₂₋₈ alkenyl; p is 0or 1; A, when bond a is present, is oxygen CH₂, N—NH₂ or N—OR⁹, where R⁹is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, C₂₋₈ alkenyl, or anaralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety; A,when bond a is absent, is OH; B is, in the case of p=1, a benzene ringhaving or not having a substituent which is halogen, hydroxyl, nitro,amino, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent, C₁₋₈haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, or an aralkyl group having aC₆₋₁₀ aryl moiety and a C1-C8 alkylene moiety of 1-8 carbon atoms, and,in the case of p=0, a condensed ring which is indole, benzofuran,benzisoxazole or 1,2-benzisothiazole, in which said condensed ring hasor does not have a substituent which is halogen, hydroxyl, nitro, amino,C₁₋₈ alkyl group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁-C₈ alkoxy substituent, C₁₋₈haloalkoxy group, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group having aC₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety; Y is bonded to the benzenering of B; (C(R³)(R⁴))_(m) is bonded to the condensed ring of B at its3-position; m is an integer of 1 to 4; n is 0, 1, 2, 3, 4, or 5; Y is abond in the case of n=0; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5),SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; and each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXIV) of Formula (V):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹¹ is hydrogen, halogen, hydroxyl, nitro, amino,cyano, carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylsubstituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxysubstituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or a C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; R¹² is hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,C₁₋₈ haloalkyl, C₁₋₈ alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈acyl, C₆₋₁₀ aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and aC₁₋₈ alkylene moiety; each of R¹³, R¹⁴, R¹⁵ and R¹⁶ independently ishydrogen, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; Y¹ is oxygen, sulfur, NR¹⁸ or abond, where R¹⁸ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, orC₂₋₈ alkenyl; A¹, when bond a is present, is oxygen CH₂, N—NH₂ orN—OR¹⁹, where R¹⁹ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl,C₂₋₈ alkenyl, or an aralkyl group having a C₆₋₁₀ aryl moiety and a C₁₋₈alkylene moiety; A¹, when bond a is absent, is OH; Q¹ is hydrogen,halogen, hydroxyl, nitro, amino, C₁₋₈ alkyl group, C₃₋₇ cycloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-memberedcycloalkyl substituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxysubstituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl grouphaving a C₆₋₁₀ aryl moiety and a C₁₋₈ alkylene moiety; r is 1, 2, 3, or4; s is 1, 2, 3, 4, or 5; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5),SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXV) of Formula (W):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R²¹ is hydrogen, halogen, hydroxyl, nitro, amino,cyano, carboxyl, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C2-C8 alkenyl, C₂₋₈alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkyl having a 3- to 7-membered cycloalkylsubstituent, C₁₋₈ haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxysubstituent, C₁₋₈ haloalkoxy, C₂₋₈ acyl, C₆₋₁₀ aryl group, a 5- or6-membered heterocyclic group, an aralkyl group having a C₆₋₁₀ arylmoiety and a C₁₋₈ alkylene moiety, or a C₁₋₈ alkyl group having a 5- or6-membered heterocyclic substituent; R²² is hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent,C₁₋₈ haloalkyl, C₁₋₈ alkyl group having a C₁₋₈ alkoxy substituent, C₂₋₈acyl, C₆₋₁₀ aryl, or an aralkyl group having a C₆₋₁₀ aryl moiety and aC₁₋₈ alkylene moiety; each of R²³, R²⁴, R²⁵ and R²⁶ independently ishydrogen, C₁₋₈ alkyl, or C₁₋₈ haloalkyl; Y² is oxygen, sulfur, NR²⁸ or abond, where R²⁸ is hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ acyl, orC₂₋₈ alkenyl; Q² is hydrogen, halogen, hydroxyl, nitro, amino, C₁₋₈alkyl group, C₃₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,C₁₋₈ alkyl having a 3- to 7-membered cycloalkyl substituent, C₁₋₈haloalkyl, C₁₋₈ alkyl having a C₁₋₈ alkoxy substituent, C₁₋₈ haloalkoxy,C₂₋₈ acyl, C₆₋₁₀ aryl, or an aralkyl group having a C₆₋₁₀ aryl moietyand a C₁₋₈ alkylene moiety; t is 1, 2, 3, or 4; u is 1, 2, 3, 4, or 5;R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXVI) of Formula (X):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl; Q¹ is CH or N; R²is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl), SO₂(C₁₋₄-alkyl), 5- or6-membered heterocycle, aryl, 5-membered heteroaryl, C≡C—R^(2A),O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, or C(O)(C₁₋₄ alkyl),wherein aryl and heteroaryl are unsubstituted or substituted withhalogen, OH, CN, C₁₋₄ alkyl, formyl, acetyl, acetoxy, or carboxy, andwherein m is 1, 2, or 3; x is 1 or 2; R^(2A) and R^(2B) are eachindependently C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl; each R²⁰is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄ alkoxy; R³is CH₃ or CD₃; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5) SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; and each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXVII) of Formula (Y):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl; Q¹ is CH or N; R²is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl), SO₂(C₁₋₄-alkyl), 5- or6-membered heterocycle, aryl, 5-membered heteroaryl, C≡C—R^(2A),O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, or C(O)(C₁₋₄ alkyl),wherein aryl and heteroaryl are unsubstituted or substituted withhalogen, OH, CN, C₁₋₄ alkyl, formyl, acetyl, acetoxy, or carboxy, andwherein m is 1, 2, or 3; x is 1 or 2; R^(2A) and R^(2B) are eachindependently C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl; each R²⁰is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄ alkoxy; R³is CH₃ or CD₃; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; and each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXVIII) of Formula (Z):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl; Q¹ is CH or N; R²is hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl), SO₂(C₁₋₄-alkyl), 5- or6-membered heterocycle, aryl, 5-membered heteroaryl, C≡C—R^(2A),O(CH₂)_(m)R^(2B), NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, or C(O)(C₁₋₄ alkyl),wherein aryl and heteroaryl are unsubstituted or substituted withhalogen, OH, CN, C₁₋₄ alkyl, formyl, acetyl, acetoxy, or carboxy, andwherein m is 1, 2, or 3; x is 1 or 2; R^(2A) and R^(2B) are eachindependently C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl; each R²⁰is independently hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄ alkoxy; R³is CH₃ or CD₃; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5) SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; and each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXIX) of Formula (AA):

or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof, wherein: L is (CH₂)₅, which is unsubstituted or substituted byone methyl group; R¹ is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or C₃₋₆ cycloalkyl; R² is hydrogen,halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃ cycloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl), SO₂(C₁₋₄-alkyl), 5- or 6-memberedheterocycle, aryl, 5-membered heteroaryl, C≡C—R^(2A), O(CH₂)_(m)R^(2B),NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, or C(O)(C₁₋₄ alkyl), wherein aryl andheteroaryl are unsubstituted or substituted with halogen, OH, CN, C₁₋₄alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or 3;x is 0 or 1; R^(2A) and R^(2B) are each independently C₁₋₄ alkyl, C₁₋₄haloalkyl, or C₃-6 cycloalkyl; R³ is C₁₋₄ haloalkyl, NO₂, CN, halogen,or C(O)O(C₁₋₄ alkyl); R²⁰ is hydrogen, halogen, C₁₋₄ alkyl, CN, or C₁₋₄alkoxy; R^(X) is CH₂OH, COH, COOCH₂CONR^(X4)R^(X5), SO₃H,

each R^(X4) and R^(X5) is independently alkyl, aryl, or heteroaryl; oralternatively, R^(X4) and R^(X5) together with the carbon atom to whichR^(X4) and R^(X5) are attached form a heterocycle; and each R^(X6) andR^(X7) is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;(XXX) having the structure:

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXI) having the structure:

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXII) having the structure:

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXIII) having the structure

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXIV) having the structure

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXV) having the structure

or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof; (XXXVI) having the structure

 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrugthereof. 2-36. (canceled)
 37. The compound or pharmaceuticallyacceptable salt of the compound of claim
 1. 38. A pharmaceuticalcomposition comprising the compound or pharmaceutically acceptable salt,solvate, ester, amide, or prodrug of the compound of claim 1 and apharmaceutically acceptable carrier or vehicle.
 39. A method fortreating or preventing a liver disorder, dyslipidemia,dyslipoproteinemia, a renal disease, a disorder of glucose metabolism, adisorder of lipid metabolism, a disorder of glucid metabolism, acardiovascular disease, a vascular disease, a metabolic syndrome, acomplication associated with metabolic syndrome, a PPAR-associateddisorder, septicemia, a thrombotic disorder, obesity, diabeticnephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, acerebrovascular disease, a disorder related to neovascularization,hypertension, cancer, inflammation, an inflammatory disease, aneurodegenerative disease, an autoimmune disease, a neoplastic disease,muscle atrophy, cholestasis, mitochondrial dysfunction, an oculardisease, a lysosomal storage disease, a kidney disease, or impotence,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of claim
 1. 40. A method fortreating or preventing hyperlipemia, hyperlipidemia,hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, ordyslipidemia, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of claim
 1. 41.A method for treating a subject having or preventing a subject fromhaving an abnormally high concentration in a subject's blood plasma orblood serum of high low-density lipoprotein (LDL), apolipoprotein B (apoB), lipoprotein(a) (Lp(a)), apolipoprotein (a), or very low-densitylipoprotein (VLDL), comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound of toclaim
 1. 42. A method for treating a subject having or preventing asubject from having an abnormally low concentration in a subject's bloodplasma or blood serum of high-density lipoprotein (HDL), comprisingadministering to a subject in need thereof an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of claim
 1. 43. A method for treating asubject having or preventing a subject from having an abnormally reducedor deficient lipoprotein lipase concentration or activity in a subject'sblood plasma or blood serum, comprising administering to a subject inneed thereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofclaim
 1. 44. A method for treating or preventinghypoalphalipoproteinemia, a lipoprotein abnormality associated withdiabetes, a lipoprotein abnormality associated with obesity, alipoprotein abnormality associated with Alzheimer's Disease, or familialcombined hyperlipidemia, comprising administering to a subject in needthereof an effective amount of the compound or the pharmaceuticallyacceptable salt, solvate, ester, amide, or prodrug of the compound ofclaim
 1. 45. A method for reducing in a subject's blood plasma or bloodserum an abnormally high concentration of triglyceride, low-densitylipoprotein cholesterol (LDL-C), very low-density lipoproteincholesterol (VLDL-C), non-high-density lipoprotein cholesterol,(non-HDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B, HDL/(VLDL+LDL)ratio, apolipoprotein C-II or apolipoprotein C-III, comprisingadministering to a subject in need thereof an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of claim
 1. 46. A method for elevating in asubject's blood plasma or blood serum an abnormally low concentration ofa high-density lipoprotein (HDL)-associated protein, HDL-cholesterol,apolipoprotein A-I, or apolipoprotein E, comprising administering to asubject in need thereof an effective amount of the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of claim
 1. 47. A method for promoting clearance oftriglyceride from a subject's blood plasma or blood serum, comprisingadministering to a subject in need thereof an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of claim
 1. 48. A method for increasingabnormally low glucose metabolism or lipid metabolism in a subject,comprising administering to a subject in need thereof an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of claim
 1. 49. A method fortreating or preventing a symptom of a disease selected frominflammation, systemic lupus erythematosus, lupus nephritis, orarthritis, comprising administering to a subject in need thereof aneffective amount of the compound or the pharmaceutically acceptablesalt, solvate, ester, amide, or prodrug of the compound of claim
 1. 50.A method for reducing the fat content of meat in livestock, comprisingadministering to livestock an effective amount of the compound or thepharmaceutically acceptable salt, solvate, ester, amide, or prodrug ofthe compound of claim
 1. 51. A method for reducing cholesterol contentof a fowl egg, comprising administering to a fowl species an effectiveamount of the compound or the pharmaceutically acceptable salt, solvate,ester, amide, or prodrug of the compound of claim
 1. 52. A method fortreating a subject with acute kidney injury (AKI) or at risk for AKI,comprising administering to the subject (i) an effective amount of thecompound or the pharmaceutically acceptable salt, solvate, ester, amide,or prodrug of the compound of claim 1.